Process for producing imidazodiazepines

ABSTRACT

This invention is directed toward pharmacologically active compound of the formula ##STR1## wherein A is ##STR2## R 1  is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, substituted phenyl, pyridyl, aralkyl and the groups ##STR3## wherein R is hydrogen or lower alkyl and ROOC where R is lower alkyl; R 2  is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower alkyl, amino or substituted amino lower alkyl, amino, cyano, cyano lower alkyl, substituted amino, chloro, bromo and iodo, the group --COOR where R is hydrogen or lower alkyl, the group ##STR4## where R is hydrogen or lower alkyl, or derivatives thereof, e.g., the group R--C═N--R&#39; wherein R&#39; is hydrogen, lower alkyl, hydroxy, phenyl, alkoxy, amino, mono or di-alkylamino and arylamino and R is hydrogen or lower alkyl, the group ##STR5## (where R and R&#39; are individually hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or together R and R&#39; form a part of a heterocyclic ring and the group (CH 2 ) n  NRR&#39; where R and R&#39; are hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl or together R and R&#39; form a part of a heterocyclic ring and n is 1 to 4); the group ##STR6## where R 10 , R 11 , R 12  are hydrogen or lower alkyl and the group (CH 2 ) n  NR 13  R 14  where n is 1 to 4 and R 13 , R 14  are hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl or R 13  and R 14  together form part of a heterocyclic ring, with the limitation that where R 10 , R 11  or R 12  is a basic side chain, then the remaining substituents are hydrogen or lower alkyl; R 3  is selected from the group consisting of hydrogen and lower alkyl; R 5  is selected from the group consisting of hydrogen, lower alkanoyloxy and hydroxy; R 4  is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl and lower alkanoyl; R 6  is selected from the group consisting of phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl and mono-substituted pyridyl; and ##STR7## is selected from the group consisting of ##STR8## and the pharmaceutically acceptable salts thereof. Also provided are methods for the preparation of these compounds as well as pharmaceutical formulations which contain the active compounds of this invention. The compounds of the formulas illustrated above and their analogs are useful as anticonvulsants, muscle relaxants, anxiolytic and sedative agents.

This is a division of application Ser. No. 905,820 filed May 15, 1978,now U.S. Pat. No. 4,280,957 which is a continuation of Ser. No. 663,660,filed Mar. 4, 1978 (now abandoned) which is a CIP of Ser. No. 602,691,filed Aug. 7, 1975 (now abandoned) which is a CIP of Ser. No. 504,924,filed Sept. 11, 1974 (now abandoned).

DESCRIPTION OF THE INVENTION

This invention relates to the pharmacologically activeimidazo[1,5-a][1,4]diazepine compounds series. The chemical structure ofthese compounds may be depicted by the following formula: ##STR9##wherein A is ##STR10## R₁ is selected from the group consisting ofhydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl,alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, substitutedamino lower alkyl, substituted phenyl, pyridyl, aralkyl and the groups##STR11## wherein R is hydrogen or lower alkyl; and ROOC where R islower alkyl; R₂ is selected from the group consisting of hydrogen, loweralkyl, hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl,halo lower alkyl, amino lower alkyl, amino, cyano, cyano lower alkyl,substituted amino, chloro, bromo or iodo, substituted amino lower alkyl,the group ROOC where R is hydrogen or lower alkyl, the group ##STR12##where R is hydrogen or lower alkyl, or derivatives thereof, i.e., thegroup ##STR13## wherein R' is hydrogen, lower alkyl, hydroxy, phenyl,alkoxy, amino, mono or di-alkylamino and arylamino and R is hydrogen orlower alkyl, the group ##STR14## (where R, R' are individually hydrogen,lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or together R andR' form a part of a heterocyclic ring and the group (CH₂)_(n) NRR' whereR and R' are hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenylor together R and R' form a part of a heterocyclic ring and n is 1 to4); the group ##STR15## where R¹⁰, R¹¹, and R¹² are hydrogen arehydrogen or lower alkyl and the group (CH₂)₂ NR¹³ R¹⁴ where n is 1 to 4and R¹³, R¹⁴ are hydrogen, lower alkyl, hydroxy lower alkyl, loweralkenyl or R¹³ and R¹⁴ together form part of a heterocyclic ring, withthe limitation that where R¹⁰, R¹¹ or R¹² is a basic side chain, thenthe remaining substituents are hydrogen or lower alkyl; R₃ is selectedfrom the group consisting of hydrogen and lower alkyl; R₅ is selectedfrom the group consisting of alkanoyloxy, hydroxy or hydrogen; R₄ isselected from the group consisting of hydrogen, halogen, nitro, cyano,trifluoromethyl, lowr alkyl, substituted amino, amino, hydroxy loweralkyl and lower alkanoyl; R₆ is selected from the group consisting ofphenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl andmono-substituted pyridyl; and ##STR16## is selected from the groupconsisting of ##STR17## and the pharmaceutically acceptable saltsthereof.

Various analogous compounds derived from the above compounds, togetherwith various novel intermediates leading to the above compounds, arealso considered to be within the scope of the invention and exhibitpharmacological activity per se or are useful intermediates topharmacologically active compounds.

Analogs of the above compounds which form a part of this inventioninclude compounds of the formula ##STR18## wherein A is selected fromthe group consisting of ##STR19## wherein V=hydrogen or lower alkyl

R₁, R₂, R₆ and ##STR20## are in Formula I above, R₇ is selected from thegroup consisting of hydrogen, lowr alkyl, lower alkenyl, lower alkynyl,acyl, hydroxy, nitroso, aromatic and aliphatic sulfonyl groups and loweralkoxycarbonyl; and R₃ is hydrogen or lower alkyl

and the pharmaceutically acceptable salts thereof.

As used in this disclosure, the term "lower alkyl" or "alkyl"comprehends both straight cyclo and branched chain (C₁ -C₇)carbon-hydrogen radicals, preferably C₁ -C₄ carbon-hydrogen radicalssuch as methyl, ethyl, propyl, isopropyl, butyl and the like.

By the term "lower alkanoyl" or "acyl" as utilized herein, an acylmoiety of a C₁ -C₇ preferably a C₁ -C₄ alkanoic acid is intended, e.g.,acetyl, propionyl, butyryl and the like, i.e., moieties of the formula##STR21## wherein R²⁰ is C₁ -C₆ or hydrogen. Also as utilized herein,the term "lower alkanoyl" comprehends a protected carbonyl such as anacetal or ketal having 2 to 7 carbon atoms, e.g., a group of the formula##STR22## wherein R²⁰ is C₁ -C₆ or hydrogen. The ketal or aldehydeprotecting group is utilized to prevent conversion of the containedketone or aldehyde ##STR23## in oxidation, reduction and condensationreactions.

The term "halogen" is used to include all four forms thereof, i.e.,chlorine, bromine, fluorine and iodine.

The terms "aromatic and aliphatic sulfonyl grouping" comprehendscompounds of the formula SO₂ X wherein X is a branched or straight chainC₁ -C₇, preferably C₁ -C₄ aliphatic group e.g., methyl or a substitutedor unsubstituted aromatic group such as a phenyl or substituted phenylderivative e.g., tolyl.

The R₆ phenyl moiety may be mono- or di-substituted provided that suchdi-substitution occurs in the 2,3; 2,5; or, most preferably, in the 2,6position of the phenyl moiety. Suitable mono-substituents includehalogen and nitro and preferably are substituted in the 2-position ofthe phenyl moiety. Suitable di-substituents are 2,6 or 2,5 di-halogenand 2,6 or 2,5 halogen-nitro. In the case of mono-substituted pyridyl,suitable substituents include halogen and nitro.

In the case of differently substituted R₃ and R₅ substituents, opticalisomerism will occur and such optical antipodes and racemates are withinthe ambit of this invention.

By the term "aryl" is meant a substituted or unsubstituted monocyclicaromatic moiety such as phenyl, chlorophenyl, tolyl, and the like. Whenvarious moieties are set herein to form a part of a heterocyclic ring,it is intended that the moieties, together with the nitrogen atom towhich they are attached form, preferably, a 5 or 6 membered ring whichcontains at the most one additional hetero atom, preferably nitrogen oroxygen as the hetero atom. Thus, by the heterocyclic ring, there isintended such moieties as morpholino, piperazino, piperidino andpyrrolidino.

By the term "alkoxy" is meant straight or branched chain saturatedhydrocarbonoxy group containing from 1 to 7 carbon atoms, preferablyfrom 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy and the like.

By the term "lower alkenyl" herein is meant straight or branched chainhydrocarbon groups which contain an olefinic double bond and have from 2to 10, preferably 2 to 6 carbon atoms, i.e., the radical of compounds ofthe formula C_(n) H_(2n) wherein n is 2-10, e.g., allyl.

By the term "substituted amino" herein is meant an --NH₂ group which maybe mono or disubstituted by lower alkyl, e.g., methylamino ordimethylamino groups or an acyl amino group e.g., acetamino which maythen be substituted on the nitrogen atom by lower alkyl or aryl e.g.,methyl, phenyl or tolyl groups or substituted carbonyloxy i.e., COORwhere R is lower alkyl or aralkyl, e.g., benzyl.

By the term "aralkyl" is meant a hydrocarbon group having both aromaticand aliphatic structures, that is, a hydrocarbon group in which a loweralkyl H atom is substituted by a monocyclic aryl group, e.g., phenyl,tolyl and the like.

Preferred compounds encompassed by the present invention include thosewherein R₁ is hydrogen or lower alkyl, preferably methyl; R₃ and R₅ arehydrogen ##STR24## is ##STR25## wherein R₄ is located preferably in the8-position of the imidazobenzodiazepine molecule and is hydrogen, nitroand halogen, preferably halogen; A is ##STR26## wherein R₆ is phenyl orhalo, nitro or lower alkyl substituted phenyl, preferably halosubstituted preferably in the 2-position of the phenyl moiety and R₂ isselected from the group consisting of hydrogen, lower alkyl, hydroxylower alkyl, e.g., hydroxy methyl, carboxylic acid hydrazide i.e., agroup of the formula --CONHNH₂ and carboxamide, i.e., a group of theformula --CONH₂ e.g., compounds of the formula ##STR27##

Thus, it is apparent from the above, an especially preferred genusincluded within the perview of the present invention encompasses acompound of the formula ##STR28## wherein R₁ is hydrogen and lower alkylpreferably methyl; R₃ and R₅ are hydrogen; R₄ is hydrogen, nitro andhalogen, most preferably, chlorine, and in a most preferred embodimentwhen positioned on the fused benzo portion of the imidazobenzodiazepineis in the 8-position thereof, R₆ is phenyl or halo, nitro, or loweralkyl-substituted phenyl, Preferably, halo, with fluorine being thepreferred halogen, the substituted fluoro being positioned in the2-position of the phenyl moiety and R₂ is hydrogen and lower alkyl.

Another preferred class of compounds falling within the scope of formulaI are those wherein R₁, R₂, R₄, R₅, R₆ and A are as in Formula IC aboveand R₃ is lower alkyl, preferably methyl, i.e., compounds of the formula##STR29##

Compounds of formula ID and their pharmaceutically acceptable saltsexhibit optical isomerism. Such a compound (ID) where R₅ =H and R₃ =CH₃has been resolved into its optical enantiomers by a procedure similar tothe one generally outlined in Advanced Organic Chemistry, L. Fieser andM. Fieser, 1961, pp. 85-88, Rheinhold Publishing Co. Both the opticalisomers and the racemic form of compound ID exhibit pharmacologicalactivity. For example, in the case of the tartrate salt of compounds offormula ID the (+) isomer is considerably more active than the (-)isomer. The less active (-) isomer may, if desired, be converted to theactive racemic form thereof such as by treatment with a non-aqueousbase, e.g., sodium tertiary butoxide in the presence of an organicsolvent in which the isomer is soluble.

A further preferred group of compounds are those of formula I wherein##STR30## is an 8-chlorophenyl or an 8-chlorothieno [3,2-f] group, R₁ ishydrogen or methyl, R₂ is acetyl, carboxamido or dimethylcarboxamido, R₆is 2 -fluoro- or 2 -chlorophenyl and R₃ and R₅ are hydrogen.

The expression "pharmaceutically acceptable salts," is used to includesalts with both inorganic and organic pharmaceutically acceptable acidssuch as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,succinic acid, tartaric acid, methanesulfonic acid, para toluenesulfonicacid and the like. Such salts can be formed quite readily by thoseskilled in the art, with the prior art and the nature of the compound tobe placed in salt form, in view.

The most preferred pharmaceutically acceptable acid addition salts ofthe compounds of formula IC and ID respectively are:

8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate;

8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate.

Also within the ambit of the instant invention are compounds which areobtained by ring opening of formula I compounds. Such compounds are ofthe formula ##STR31## wherein X⁻ is the anion of an organic or inorganicacid, and R₁, R₂, R₃, R₄, R₅, R₆ and ##STR32## are as in formula I. Ithas been found that certain compounds of Formula I in solution open tocorresponding compounds of Formula IE. Such open compounds exist in apH-dependent equilibrium in solution with compounds of Formula I, i.e.,their corresponding ring closed compounds. The compounds of Formula IEcan be isolated as acid addition salts by treatment of theircorresponding closed ring compounds with an aqueous mineral acidfollowed by evaporation of solvent. When isolated, these salts exhibitpharmacological activity comparable to their corresponding closed ringparents.

The compounds of formula I above including the preferredimidazobenzodiazepines of formulas IC and ID can be prepared following avariety of synthetic routes including the following novel processaspects which form a part of the present invention.

In one of the aforementioned novel process aspects of this invention,the compounds of formula I above may be prepared by the nitrosation of acompound of the formula ##STR33## wherein A is ##STR34## R₃ is hydrogenor lower alkyl and ##STR35## R₄ and R₆ are as described in Formula I, toproduce a compound of the formula ##STR36## wherein A, R₃, R₄, R₆ and##STR37## are as described in Formula II.

Such a nitrosation may be affected by "in situ formed" nitrous acid.Reagents which may be employed include (1) alkali metal nitrites, i.e.,sodium nitrites, in the presence of organic or inorganic acids, i.e.,glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkylnitrites, i.e., methyl nitrites, in the presence of an inert solventsuch as alcohol, chlorinated hydrocarbon or, for example,dimethylformamide; and (3) a nitrosyl chloride gaseous solution in aninert solvent and in the presence of an acid acceptor such as pyridine.Such a nitrosation reaction should be affected at around or below roomtemperature, i.e., in the range of -20° C. to 25° C.

The 2-position nitrosoalkylamine, e.g., ##STR38## represents a "leavinggroup." Equivalent leaving groups which may be utilized as 2-positionsubstituents include groups such as alkoxide, e.g., --OCH₃ ; alkylthio,e.g., --SCH₃ ; halo, e.g., chloro; cyano, e.g., --CN, and phosphate,e.g., ##STR39## Reactions which form the alkoxide and alkylthio2-position substituents are well known in the art; see, for example, G.A. Archer and L. H. Sternbach, Journal of Organic Chemistry, 29, 231(1964) and U.S. Pat. No. 3,681,341, issued Aug. 1, 1972 to Fryer et al.

Compounds of formula III may then be condensed with a nitroalkane toform a novel intermediate of the formula ##STR40## wherein R₂ ishydrogen or lower alkyl, A, R₃, R₄, R₆ and

are as described in Formula II

The condensation reaction is affected with a nitroalkane, (R₂ --CH₂--NO₂), where R₂ is hydrogen or lower alkyl, i.e., nitromethane,nitroethane, etc., in the presence of a base which is strong enough togenerate the nitroalkane anion. Suitable bases include the alkali metalor alkaline earth metal alkoxides, e.g., potassium tertiary butoxide,amides, e.g., lithium amide or hydrides, e.g., sodium hydride. Thereaction is preferably carried out in an inert solvent, such asdimethylformamide, dimethylsulfoxide, or an ether, e.g., THF, attemperatures below or above room temperature, i.e., in the range of -50°C. to 150° C., preferably at about room temperature.

The novel compounds of formula IV and formula V below, besides beingmajor intermediates in the synthesis of compounds of formula I, alsoexhibit activity as central nervous system depressants.

Compounds of formula IV may then be catalytically hydrogenated, forexample, with Raney nickel in the presence of hydrogen or by otherreductants such as lithium aluminum hydride (with limitation that A isnot N-oxide) to produce a compound of the formula ##STR41## wherein A is##STR42## R₃, R₄, ##STR43## and R₆ are as in Formula II except that R₄is not nitro or cyano, and R₆ is not nitro substituted and R₂ ishydrogen or lower alkyl.

The exclusion of nitro and cyano above from the substituent groupspresent results from the conversion of nitro into amino and cyano intomethylamino under the reaction conditions employed in the step IV→V.

Solvents suitable for hydrogenation with Raney nickel include alcohols,e.g., ethanol, ethers, e.g., THF, diethylether, etc., hydrocarbonsolvents, e.g., toluene and dimethylformamide. The reaction temperaturemay be above or below room temperature (i.e., -50° C. to 150° C.) andthe reaction may be carried out with or without pressure, i.e., pressureof one atmosphere or higher.

Solvents suitable for hydrogenation employing a reductant such aslithium aluminum hydride include ethers, e.g., THF, dioxane,diethylether and mixtures of ethers and hydrocarbon solvents, e.g., THFand benzene. The reaction may be carried out from below room temperatureto reflux temperature, i.e., preferably in the range of -50° C. to 60°C.

The compounds of formula V may then be acylated with an acylating agentsuch as an acid halide or acid anhydride, i.e., a group of the formula(R₁ CO)₂ O wherein R₁ is hydrogen, lower alkyl, phenyl, pyridyl,substituted phenyl, alkoxy lower alkyl and aralkyl, e.g., aceticanhydride and acetyl chloride to produce a compound of the formula##STR44## wherein A, R₂, R₃, R₄, ##STR45## are as described in FormulaV, R₁ is hydrogen, lower alkyl, phenyl, pyridyl, substituted phenyl,alkoxy lower alkyl and aralky and Y is hydrogen or --COR₁.

In acylating the compounds of formula V to compounds of formula VI,there may be present a mixture consisting of the predominantmonoacylated product, i.e., wherein the NH₂ group of V (position 2) isconverted to NHCOR₁, and the diacylated product wherein both the NH₂ ofV (position 2 ) and 1-position nitrogen are acylated. The yield ofdiacylated product may be increased by subjecting the compounds offormula V to more rigorous conditions, i.e., excess of acylating agentand increased reaction time. It should be noted where any of thesubstituents may be hydroxy lower alkyl that this substituent should beprotected by, for example, esterification a subsequent mild hydrolysiswill reconvert the protected substituent to the original substituent.

The acylation is preferably carried out in the presence of an aqueous ornon-aqueous solvent e.g., water, methylene chloride, benzene,chloroform, etc., and preferably with an acid acceptor such as anorganic or inorganic base such as triethylamine, pyridine or an alkalimetal carbonate. The compounds of formula VI may then be cyclized tonovel compounds of the formula ##STR46## wherein A, R₁, R₂, R₃, R₄ and##STR47## are as described in formula VI.

The cyclization reaction is affected with a dehydrating agent such asphosphorus pentoxide, polyphosphoric acid or other suitable acidcatalysts, i.e., organic or inorganic acids, e.g., conc. H₂ SO₄. Asolvent is not required but a solvent such as an aromatic hydrocarbonsolvent, e.g., toluene, xylene, may be employed. The reaction is carriedout at a temperature range of from about 100° C. to 200° C.

The compounds of formula V may also be reacted with an acylating agentsuch as an orthoester, e.g., triethylorthoacetate, an orthoamide, e.g.,the dimethylacetal of N,N-dimethylformamide, or a compound of theformula ##STR48## optionally in the presence of an acid catalyst, e.g.,an organic or inorganic acid, e.g., p-toluene sulfonic acid, phosphoricacid, etc., and at room temperature or above, i.e., 25° C. to 150° C.,in which instance the cyclization to compound VII occurs spontaneously.Other useful acylating agents include esters, e.g., methyl acetate;amidines, e.g., acetamidine; nitriles, e.g., acetonitrile and esterimidates, e.g., a compound of the formula ##STR49##

The compounds of formula VII may then be dehydrogenated to yieldcompounds of the formula ##STR50## wherein A, R₁, R₂, R₃, R₄ and##STR51## are as described in formula VI.

Preferred reactants for the dehydrogenation (VI→VII) include manganesedioxide and palladium on carbon although potassium permanganate may alsobe utilized. Solvents which may be utilized include chlorinatedhydrocarbon solvents, aromatic hydrocarbons, dimethylformamide, etc. Thedehydrogenation is carried out at room temperature or above, i.e., inthe range of about 25° C. to 200° C.

The novel compounds of formula VII also exhibit activity as centralnervous depressants and form part of this invention.

The above novel process may proceed, if desired, from intermediatecompounds IV or V to compounds of formula IF without the requirement ofisolating any formed intermediate compounds before proceeding to thenext process step.

It should be noted in acylating the compounds of Formula V to thecompounds of Formula VI when R₄ is amino or alkyl amino that the aminomay also be acylated to acylamino. The acylamino may be converted backto amino or alkylamino by subjecting the compounds of Formula VII or IFto a mild hydrolysis.

Also within the ambit of this invention, it has been found thatcompounds of the formulas IV, V, VI and VII may exhibit both optical andgeometric isomerism.

The reaction of a compound of the formula V with acetic acid and zinc orany other suitable reductants e.g., hydrogen in the presence of acatalyst e.g., platinum in dilute acetic acid solution, produces acompound of the formula ##STR52## wherein A is ##STR53## R₂, R₃, R₄,##STR54## and R₆ are as in formula V.

Depending on the above method of reduction chosen, formula V' when R₂ ishydrogen can be isolated as a recemic mixture of either of the twopossible diastereomers.

A compound of the formula V' may be converted to its dihydimidazoderivative of the formula ##STR55## wherein A, R₂, R₃, R₄ and ##STR56##are as in formula V' and R₁ is as in formula VI with retention ofstereochemistry, by utilizing the direct reaction set forth above, i.e.,the reaction of formula V compounds with an acylating agent such as anorthoester e.g., triethylorthoacetate and maintaining the reactionparameters set forth above for such a reaction.

Compounds of formula VII' can also be prepared by reduction of acompound of formula VII by utilizing reductants as mentioned above e.g.,acetic acid and zinc or H₂ /platinum catalyst in dilute acetic acid,with the particular stereoisomer produced dependent on the reductantchosen.

Compounds of the formula VII' can, if desired, be oxidized directly toanalogous compounds of the formula I using an oxidant such as manganesedioxide in toluene or benzene solution. Reaction conditions utilized andvarious alternate useful oxidants are found in U.S. Pat. No. 3,322,753issued May 30, 1967 to Fryer et al.

Another process to produce the novel intermediates of formula V where R₄and R₆ are other than nitro or cyano consists of the reduction ofcompounds of the formula ##STR57## wherein A is ##STR58## and R₃, R₄,##STR59## and R₆ are as described in formula II except that R₄ is notnitro or cyano and R₆ is not nitro-substituted.

The reduction comprises the reaction of the compounds of formula X witha known reductant such as Raney nickel in the presence of hydrogen or byother reductants such as lithium aluminum hydride. Solvents suitable forhydrogenation with Raney nickel include alcohols e.g., ethanol etherse.g., THF, hydrocarbon solvents e.g., toluene, and dimethylformamide.The reaction temperature may be above or below room temperature (i.e.,-50° C. to 150° C.) and the reaction may be carried out with or withoutpressure, i.e., pressure of one atmosphere or higher.

Solvents suitable for hydrogenation employing a reductant such aslithium aluminum hydride include ethers, such as dioxane, diethyl etherand THF. The reaction may be carried out from below room temperature toreflux temperature i.e., preferably in the range of -50° C. to 60° C.

A variation of the above process comprises a mild acid hudrolysis of thecompounds of formula X to produce compounds of the formula ##STR60##wherein A, R₄, R₃, ##STR61## and R₆ are as in formula X.

The mild acid hydrolysis is suitably affected by a dilute mineral acid,e.g., aqueous H₂ SO₄ in aqueous alcohol. The reaction temperature mayrange from room temperature, i.e., about 25° C. to above roomtemperature, i.e., about 60° C. The compounds of formula XI may then bereduced to the novel intermediates of formula V.

Another process, although it does not form a part of the presentinvention, is useful in producing the novel intermediates of formulas IVand V. The following process is included in this specification for thesake of unity.

The compounds of formula IV above may be produced by the successivereaction of the compounds of the formula ##STR62## wherein A, ##STR63##R₃ and R₄ are as in formula II with dimorpholinophosphinic chloride toproduce compounds of the formula ##STR64## wherein A, ##STR65## R₃ andR₄ are as in formula XII; which imino phosphates are then displaced bythe anion of a nitroalkane to produce the novel intermediates ##STR66##wherein A, ##STR67## R₃ and R₄ are as described in formula XII.

The displacement reaction is affected with nitroalkane, i.e.,nitromethane, nitroethane, etc., in the presence of a base which isstrong enough to generate the nitroalkane anion. Suitable bases includethe alkali metal or alkaline earth metal alkoxides, hydrodes, amides orhydroxides. The reaction is preferably carried out in an inert solvent,such as dimethylformamide, dimethylsulfoxide, or an ether, attemperatures below or above room temperature, i.e., in the range of -50°C. to 150° C.

Another process to produce intermediates of formula IV wherein R₂ ishydrogen and A is an N-oxide comprises the ring expansion of compoundsof the formulae ##STR68## wherein A is ##STR69## R₆, ##STR70## R₃ and R₄are as described in formula II except that R₄ is not amino orsubstituted amino.

The ring expansion comprises the reaction of the compounds formulae VIIIor IX with nitromethane in the presence of a base strong enough togenerate the nitromethane anion. Suitable bases include the alkali metaland alkaline earth mertal alxoxides e.g., potassium tertiary butoxide,amides e.g., lithium amide or hydrides e.g., sodium hydride. Thereaction may be preferably carried out in an inert solvent such asanhydrous ether e.g., THF, dimethylformamide, dimethylsulfoxide, etc.and at a temperature in the range of about -20° C. to 25° C.

Compounds of the formula IA wherein A is ##STR71## may be formed byisomerization of the 5,6-double bond in Formula I compounds to the4,5-position. Formula IA compounds may be formed by the treatment offormula I compounds with an anhydrous base in the presence of an inertorganic solvent.

All that is required of the base is that it be suitable for the purposesof the present invention, that is, that it effect the conversion of acompound of formula I above to the corresponding compound of the formulaIA above. Among the many suitable bases can be included alkali metallower alkoxides, such as sodium methoxide, potassium tertiary butoxideand the like and alkali metal hydrides, such as sodium hydride.

Representative, but by no means exclusively so, of inert organic solventsuitable for the purpose of the present invention are dimethylformamide,dimethylsulfoxide, tetrahydrofuran and the like. Here again, temperatureand pressure are not critical aspects of this conversion step. However,it has been observed that temperatures of from about 31 50° C. to about80°, most preferably from about -30° to 25° C. are useful.

Compounds of the formula IA where A is ##STR72## are formed by theconversion of corresponding formula I compounds into the N-oxidesthereof. This conversion is affected by oxidizing a formula I compoundwith an organic peracid. A conventional organic peracid, such asperacetic acid, perpropionic acid, m-chloroperbenzoic acid, etc., can beutilized in carrying out this reaction. The oxidation can be affected atroom temperature, or above or below room temperature.

Compounds of the formula IA where A is ##STR73## may be then utilized toproduce compounds of formula I wherein R₅ is alkanoyloxy or hydroxy bymethods known in the art, such as, for example, a Polonvskirearrangement utilizing an acid anhydride to form the alkanoyloxyradical which may be converted to the hydroxy by treatment with analkali metal hydroxide such as sodium hydroxide. An example of such aPolonovski rearrangement is found in U.S. Pat. No. 3,296,249 issued Jan.3, 1967 to S. C. Bell.

Compounds of the formula IA where A is ##STR74## are formed by thereduction of corresponding formula I compounds to compounds of theformula ##STR75## ##STR76## are as in formula I with the exception thatR₄ is not nitro and R₆ is not nitro-substituted (since nitrosubstituents may be reduced to amino under the reaction conditions),which may be then converted to compounds of the formula ##STR77##wherein R₁, R₂, R₃, R₄ and R₆ are as in formula IA' and R₇ is hydroxy,acyl or an aromatic or aliphatic sulfonyl group.

The reduction of formula I compounds to IA' compounds is accomplished byany suitable reducing agent but most preferably accomplished by hydrogenin the presence of a platinum oxide catalyst or zinc in the presence ofacetic acid. These compounds (IA') may be converted to IA" compoundshaving an R₇ -radical other than hydroxy by reaction with a member, forexample, from the group comprising a lower alkyl halide, e.g., methyliodide lower alkenyl halide, e.g., allyl bromide, lower alkynyl halide,e.g., propargyl-bromide, alkyl or aryl sulfonyl halide, e.g., tosylchloride, mesyl chloride, nitrosyl chloride and a lower alkanoyl groupproviding agent, e.g., acetyl chloride. Also used above the term "loweralkynyl" includes unsaturated straight and branched chaincarbon-hydrogen radicals which contain triple bonds, i.e., the radicalcompounds of the formula C_(n) H_(2n-2) wherein n is 3-7, e.g.,propargyl.

This process aspect is conveniently effected in the presence of an inertorganic solvent such as an alkanoyl, e.g., ethanol and methanol, anether such as diethyl ether and tetrahydrofuran, dimethylformamide andthe like. Suitably, an acid acceptor is provided to the reaction zone toaccept the hydrogen halide formed when utilizing a halide, e.g., an arylsulfonyl (e.g., tosyl) halide or an alkyl sulfonyl (e.g., mesyl) halide,with a compound of the formula IA' above. Suitable acid acceptors aretertiary amines, e.g., triethylamine, pyridine and the like.

Temperature and pressure are not critcial aspects of the first stage ofthe process involving the conversion of the compound of the formula Iabove to the corresponding compound of the formula IA. However, thereaction is most preferably effected at about room temperature andatmospheric pressure for the preparation of compounds IA' and roomtemperature and above for the conversion of compounds IA' to IA" bearingan R₇ radical other than hydroxy.

Reduction of IA compounds wherein A is ##STR78## with hydrogen in thepresence of platinum catalyst and acetic acid leads to IA" compoundswherein R₇ is hydroxy.

Compounds of formula IA" wherein R₇ is hydroxy, may be converted to thecorresponding formula I unsaturated imine by treatment of the IA"compound with an acetic anhydride/pyridine mixture. No other solvent isnecessary for this reaction and temperature is not critical although thereaction is best effected at room temperature.

Compounds of formula IA" above wherein R₇ is acetyl, mesyl or tosyl maybe converted to the corresponding formula I unsaturated imine bytreatment of the IA" compound with a non-aqueous base, e.g., potassiumtertiary butoxide, in the presence of an inert solvent e.g., THF, DMF,etc. Such as reaction and the conditions at which it is run are wellknown in the art, see, for example U.S. Pat. No. 3,625,957 issued Dec.7, 1971 to Fryer et al.

Compounds of Formula IA' above may be converted to the analogous formulaI unsaturated compounds by oxidation of the secondary amine at the5-position. Such a selective oxidation may be accomplished by knownoxidants and reaction schemes see, for example, U.S. Pat. No. 3,322,753, issued May 30, 1967 to Fryer et al.

Conversion of compounds of formula I which contain a Schiff base at the5,6-position wherein R₄ is amino to compounds wherein R₄ is nitro may besuitably affected by, for example, the Sandmeyer Reaction wherein theamino group is replaced by a nitro group, for example by the treatmentof a formula I compound wherein ##STR79## is an amino substituted benzomoiety, with excess sodium nitrite in the presence of a coppersulfate/sodium sulfite mixture and utilizing as a solvent dilutesulfuric acid.

The resulting intermediate of the formula ##STR80## wherein R₁, R₂, R₃,and R₆ are as in formula I may then be converted to an analogous formulaI compound. This process may be effected in a two-step sequence withoutisolation of the intermediate XXIV formed by treatment of the aboveformula XXIII' compound or its analogous diazepine of formula I withphosphorus tribomide in an inert organic solvent e.g., dichloromethaneat about -10° to 25° C. (although temperature is not critical) and thensubsequent treatment in situ with ammonia, preferably liquid ammoniawhich is allowed to warm to room temperature.

The Sandmeyer reaction has been found to also be applicable in producingcompounds which contain a cyano, chloro or bromo in place of a nitrogroup. Such corresponding compounds of formula XXIII' can be convertedto their ring closed analogs in the same manner as described above fornitro compounds.

It should be noted that certain compounds which contain a Schiff base atthe 5,6-position may not readily open to a XXIII' type compound. Thesecompounds proceed directly to the desired analogous formula I compoundswherein R₄ is nitro. Similarly, the above Sandmeyer reaction may beutilized to convert R₄ =amino to R₄ =cyano. As above, both analogousXXIII' type compounds and closed compounds may be present.

It should be noted and be obvious to one skilled in the art that certainoother substituents which may be present as R₁, R₂, R₃ and R₆substituted may also be attacked during the above reactions, such as,for example, where R₁ or R₂ are a primary amine, alcohols, carboxylicacids or esters thereof, etc., but such vulnerable groups may be blockedby a suitable protecting group or modified before the above reactionsequence is carried out. Such methods of modifying or protecting groupssubject to attack are well known in the art. Further, certain of thesubstituents which might be attacked during the above reaction sequenceand reaction sequences set forth throughout this application may bereconverted to the original substituents utilizing methods known in theart or disclosed herein.

Compounds of the formula IA where A is ##STR81## and wherein V ishydrogen or methyl, may be formed by the direct reaction of formula Icompounds with ethylene oxide or propylene oxide in the presence of aLewis acid catalyst or where V is lower alkyl or hydrogen by thereaction of a compound of the formula ##STR82## wherein R₁, R₂, R₃,##STR83## and R₆ are as in formula I except that R₄ is not amino orsubstituted amino with phosphorus tribromide and subsequent treatment ofthe intermediate (XXIV) with a compound selected from the groupconsisting of ethanol amine, a 1-alkyl substituted ethanolamine and a2-alkyl substituted ethanolamine as shown in the following reactionscheme: ##STR84##

The compounds of formula XXIII may be formed by the reaction of acompound of the formula IE with sodium nitrite in the presence of acompatible solvent such as water or dilute mineral acid. The temperatureof the reaction may be -10° C. to room temperature. The reaction offormula XXIII compounds with phosphorus tribromide is effected asillustrated above, preferably in an inert organic solvent such asdichloromethane at about room temperature although such temperature isnot critical.

The reaction of the compound of formula XXIV with ethanolamine or1-alkyl or 2-alkyl substituted ethanolamine is effected in situ, i.e.,with a suitable inert solvent such as dichloromethane, at a temperaturerange of -10° C. to reflux, with about room temperature preferred.

The direct reaction of formula I compounds with ethylene oxide orpropylene oxide is preferably catalyzed by a Lewis acid, e.g., titaniumtetrachloride, boron trifluoride, etc.

In compounds of formula I and their analogs wherein the ketal group,e.g. ##STR85## is present as a 8-position substituent in animidazobenzodiazepine, such ketal group may be converted to an8-position ketone by subjecting the ketal roup to a mild acidhydrolysis. The 8-ketone can then be converted to a 8-position secondaryor tertiary alcohol which is racemic in nature. The reaction conditionstherefor, for the above two steps, are found in U.S. Pat. No. 3,846,410issued Nov. 5, 1974.

As stated above compounds of formula I may be directly reacted withethylene oxide or propylene oxide to produce formula IA compounds, i.e.,oxazolo type compounds. Reaction parameters and conditions to effectsuch a reaction are known in the art, see for example U.S. Pat. No.3,868,362 issued Feb. 25, 1975 to Fryer et al and U.S. Pat. No.3,905,956 issued Sept. 16, 1975 to Derieg et al.

Yet another process to produce the compounds of formula I consists ofthe following reaction scheme: ##STR86##

In the above reaction scheme unless otherwise indicated R is loweralkyl, R₁, R₃, R₄ and R₆ are as in formula I and A is as in formula Ibut may also be ##STR87## but any N-oxide moiety present in the abovereaction scheme will be removed during the reaction stepXVI→XVII+isomers.

It is obvious to one skilled in the art that certain of the substituentsmay be attacked during the above reactions but such vulnerable groupsmay be protected or modified prior to the above reactions or if allowedto be attacked may be reconverted to the original substituent utilizingwell known methods after such reaction is carried out.

XIII or III→XIV--Compounds of formula XIII may be condensed with theanion generated from malonic ester e.g., of the formula ##STR88## toproduce compound of formula XIV. The anion is generated by deprotonatingmalonic ester with a suitable strong base such as alkali metal oralkaline earth metal alkoxides, hydrides or amides. The reaction of theformula XIII or III compounds with the malonic ester anion is preferablyeffected in a solvent such as hydrocarbons, e.g., benzene, toluene,hexane, ethers, e.g., dioxane, THF, diethyl ether, DMF, DMSO etc., at arange of below room temperature to 150° C., preferably 0° C. to 100° C.,most preferably room temperature. It should be pointed out that anyamino or substituted amino group may be present in protected form inthis reaction step. The protected moiety can be removed afterwards atany convenient stage, for example, subsequent to formation of formulaXVIII compound.

XV→XVI--Compounds of formula XVI are produced by the nitrosation ofcompounds of formula XV by reacting same with nitrous acid generatedfrom, for example, an alkali metal nitrite, alkyl nitrite or nitrosylchloride, by reaction with organic or inorganic acid. Suitable solventsfor the nitrosation reaction include ethers, alcohols, water, acids,e.g., acetic acid, DMF, DMSO and chlorinated hydrocarbons. The reactionmay be carried out at about room temperature although such temperatureis not critical.

XVI→XVII+XVII A,B,C and D--Compounds of the formula XVII are produced bythe reduction of compounds of formula XVI with Raney nickel and hydrogenor with zinc and acetic acid. This reduction results in the predominantproduction of compounds of formula XVII with concurrent side productionof small amounts of several possible isomers, i.e., compounds of theformulas XVII A, B, C and D. It should be noted that the above reductivestep would remove any N-oxide moiety present on the 4-position nitrogenand would reduce vulnerable groups, if present, as R₄, such as, a7-position NO₂, or a 7-position CN. These groups may be subsequentlyreplaced by methods known in the art, for example, a compound of formulaXVII wherein R₄ is amino can be converted to corresponding compoundswherein R₄ is nitro or cyano via a Sandmeyer reaction as set forth inthis specification.

A method for preparing compounds of formula XVII, particularly, whereinR₄ is nitro or cyano consists of, for example, in the conversion of aformula XIX compound, shown in the above reaction scheme, wherein R₁ isbenzyloxy or any other equivalent protecting group which may be cleaved,e.g., carbobenzoxy group, and R is lower alkyl. The conversion consistsof cleavage of the R₁ substituent by reaction with HBr in acetic acid.The reaction may be run at from 0° C. to 100° C. most preferably atabout room temperature in an inert solvent such as hydrocarbons, e.g.,benzene, toluene, hexane, etc., or chlorinated hydrocarbons or, ifdesired, in acetic acid alone.

XIV→XV--Compounds of formula XV are formed decarboxylation of compoundsof formula XIV by reacting formula XIV compound with an alkali metalhydroxide e.g., NaOH or KOH in a suitable solvent e.g., alcohols, ethersor DMSO at a temperature range of from temperature to refluxtemperature, preferably 60° C. to 100° C.

XVII→XIX--Compounds of formula XIX may be formed by the acylation offormula XVII compounds with a compound of the formula:

    R.sub.1 COX or (R.sub.1 CO).sub.2 O

wherein X is halo and R₁ is hydrogen, lower alkyl, phenyl, alkoxy loweralkyl, substituted phenyl, pyridyl or aralkyl.

Solvents for the above process step include methylene chloride, ethers,chlorinated hydrocarbons, etc., preferably in combination with an acidacceptor such as an organic or inorganic base such as triethylamine,pyridine or an alkali metal carbonate. The reaction may be effected atabove or below room temperature but preferably is carried out at roomtemperature. Compounds of the formula XIX are isomeric in nature, thatis, may exhibit either of the following stereochemical structures##STR89##

XVII→XVIII--Compounds of the formula XVIII are then formed by thereaction of formula XVII compounds with an alkanoic acid ortho ester ofthe formula:

    R.sub.1 C(OR).sub.3

wherein R is lower alkyl and R₁ is hydrogen, lower alkyl, alkoxy loweralkyl or halo lower alkyl or its equivalents, e.g., ortho amides, thedimethylacetal of N,N dimethylformamide, N,N,N',N', N",N"-hexamethylmethane triamine, or nitriles, such as, acetonitrile, and ester imidatese.g., ##STR90## following the disclosed reaction conditions andparameters set forth previously in the specification wherein formula Vcompounds are directly converted to formula VII compounds.

XVII→XX--Compounds of the formula XX are formed by the reaction offormula XVII compounds with an aldehyde of the formula R₁ CHO wherein R₁is as in formula I, but any amino, substituted amino and preferably anyRCO group should be present in protected form. The protecting moiety canbe removed afterwards, e.g., subsequent to the formation of formulaXVIII compounds. Solvents suitable for this reaction step arehydrocarbons such as benzene, alcohols, ethers, chlorinatedhydrocarbons, DMF, DMSO, etc., with or without the presence ofwater-binding agents, e.g., molecular sieves at above or below roomtemperature, preferably from room temperature to reflux temperature ofthe solvent.

XX→XVIII--Compounds of the formula XX may be converted to formula XVIIIcompounds by oxidation in situ by oxidizing agents such as manganesedioxide, air, oxygen, etc.

XIX→XVIII--Compounds of the formula XVIII may also be formed by thedehydration of formula XIX compounds or isomers thereof with concurrentcyclization by heating. In this reaction step, R₁ is restricted tohydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl,pyridyl and aralkyl. This reaction step may be carried out with orwithout solvent, e.g., DMF, ethylene glycol, hexamethyl phosphorictriamide, at a temperature range of 100° C. to 300° C., preferably at150° C. to 250° C., e.g., 200° C., with or without the presence ofcatalysts and water binding agents. Compounds of the formula XVIII mayalso be formed from formula XIII compounds in situ without isolation ofcompounds of the formulae XXI and XIX.

XIII→XXI--Compounds of the formula XXI may be formed by the condensationreaction of a compound of the formula XIII with the anion generated fromacyl amino malonic ester of the formula ##STR91## wherein R is loweralkyl and R₁ is hydrogen, lower alkyl, alkoxy lower alkyl, substitutedphenyl, phenyl, pyridyl, aralkyl, benzyloxy, i.e., OCH₂ C₆ H₅

to produce compound of formula XXI. The anion is generated bydeprotonating acylamino malonic ester with a suitable strong base suchas alkali metal or alkaline earth metal alkoxides, hydrides or amides.The reaction of the formula XIII compounds with the acyl amino malonicester anion is preferably effected in a solvent such as hydrocarbonse.g., benzene, toluene, hexane, ethers, e.g., dioxane, THF, diethylether, DMF, DMSO etc., at a temperature range of below room temperatureto 150° C., preferably 0° C. to 100° C., most preferably roomtemperature.

XXI→XIX--Compounds of formula XIX and isomers thereof are formed by thedecarboxylation of formula XXI compounds with an alkali metal alkoxidein a solvent such as ethers, alcohols, DMSO, DMF, etc., at above orbelow room temperature, preferably at room temperature.

The following general reaction scheme is illustrative of several of thereactions of the intermediate compound of formula XVIII to producecompounds of the formula I. It is obvious to one skilled in the art thatcertain of the substituents may be attacked during the below reactionsbut such vulnerable groups may be modified before or reconverted afterthe below reaction sequence is carried out.

In the below reaction schemes, unless otherwise indicated, R is loweralkyl. ##STR92##

XVIII→XXII--Formula XXII compounds are formed by hydrolyzing formulaXVIII compounds to the corresponding acids, preferably with alkali metalhydroxides, e.g., NaOH or KOH. This hydrolysis is conveniently effectedin an inert solvent. Suitable solvents are alcohols, e.g., methanol,ethanol; ethers, e.g., dioxane, tetrahydrofuran; dimethylformamide, incombination with water. It is preferable to conduct this reaction stepat a temperature between room temperature and the boiling point of thereaction mixture.

It is evident that during this reaction step an acyloxyalkyl grouppresent will be hydrolyzed to the corresponding hydroxyalkyl group whichin turn can be converted back to the acyloxyalkyl group at a convenientlater stage. An R₁ - group having the meaning of --COOR will also behydrolyzed and decarboxylated to a corresponding compound wherein R₁ ishydrogen. The --COOR moiety can be reintroduced from a formyl orhydroxymethyl group in known manner. A haloalkyl group present may beaffected in this reaction step yielding a corresponding hydroxyalkylcompound which may also be converted back to the halo alkyl compound ata later stage in usual manner. Any compound of formula XVIII wherein R₄is hydroxyalkyl should be protected during this halogenation reactionstep, e.g., in form of the tetrahydropyranylether derivative thereof.

XVIII→XXIII--Formula XXIII compounds are formed by the reduction offormula XVIII compounds, preferably with lithium aluminum hydride or anequivalent reducing agent. This reduction is conveniently conducted inan inert solvent. Suitable solvents are hydrocarbons, e.g., hexane,toluene; ethers, e.g., diethylether, tetrahydrofuran, dimethoxyethane;or mixtures thereof. It is preferable to perform this reduction at atemperature between about -50° C. and the boiling point of the reactionmixture, most preferably between about -20° C. and 0° C.

Nitro and cyano groups present may be affected during this reactionstep. Such groups can be formed at a later stage of the synthesisutilizing methods of reconversion previously discussed.

XXIII.increment.XXIV--Compounds of formula XXIII can be converted tocompounds of formula XXIV by acylation with acid anhydrides or acidchlorides in presence or absence of an acid acceptor. This acylation isconveniently conducted in an inert solvent. Suitable solvents arehydrocarbons, e.g., hexane, toluene; chlorinated hydrocarbons, e.g.,methylene chloride; ethers, e.g., tetrahydrofuran; dimethylformamide.Preferably this acylation is conducted at a temperature between about-50° C. and 150° C., most preferably at room temperature. Acid acceptorsthat can be used in this reaction step are for instance pyridine,triethylamine, potassium carbonate.

It is evident that any substituent present as R₁ and/or R₄ and liable tobeing acylated during this reaction step should be protected in theusual manner in order to avoid any undesired acylation of such groups.

XXIII→XXV--Compounds of formula XXV can be prepared by oxidation offormula XXIII compounds by known oxidants such as chromium trioxide andmanganese dioxide. This oxidation is conveniently conducted in an inertsolvent. Suitable solvents are hydrocarbons, e.g., hexane, toluene;chlorinated hydrocarbons, e.g., methylene chloride; ketones, e.g.,acetone; organic acids, e.g., acetic acid; pyridine, dimethylformamide,dimethylsulfoxide. The oxidation is preferably performed at atemperature between about -50° C. and the boiling point of the reactionmixture, most preferably at about 0° C. and room temperature.

It is evident that any substituent present as R₁ and/or R₄ ashydroxyalkyl must be protected in the usual manner during this reactionstep.

XXIII→XXVI--Compounds of formula XXVI are prepared by substitution ofhydroxy group in the 3-substituent of formula XXIII compounds with ahalogen. This reaction is preferably carried out by reagents such as aphosphorous halide, e.g., phosphate trichloride, phosphorous tribromideor thionyl chloride. This reaction step is conveniently conducted in aninert solvent or in the absence of a solvent. Suitable solvents arehydrocarbons, e.g., hexane, toluene; chlorinated hydrocarbons, e.g.,methylene chloride; ethers, e.g., tetrahydrofuran. The temperature atwhich this reaction step is performed is preferably situated betweenabout -50° C. and 100° C., most preferably between about 0° C. and roomtemperature.

It is evident that any R₁ /R₄ hydroxyalkyl group should be protected incase a conversion into the corresponding haloalkyl derivative is deemedundesirable.

XXVI→XXVII; XXVIII; XXIX--Compounds of formula XXVI can be reacted suchthat the halogen in the 3-substituent is nucleophilically displaced byother nucleophilic groups such as an amine (XXVII, wherein R' ishydrogen or lower alkyl and R" is hydrogen, lower alkyl or acyl),alkoxide (XXVIII) and cyanide (XXIX).

In the reaction step XXVI→XXVII a compound of formula XXVI is treatedwith ammonia or a mono- or dialkylamine. A compound obtained wherein R;and/or R" is hydrogen can, if desired, be acylated with a suitableacylating agent. This reaction step can be effected in the absence or inthe presence of an inert solvent. Suitable solvents are hydrocarbons,e.g., hexane, toluene; chlorinated hydrocarbons, e.g., methylenechloride, chlorobenzene; ethers, e.g., diethylether, tetrahydrofuran;dimethylformamide, dimethylsulfoxide. This reaction is preferablyconducted at a temperature between about 0° C. and the boiling point ofthe reaction mixture with or without applying pressure above atmosphericpressure.

It is evident that a compound of formula XXVII wherein R₁ is haloalkylhas to be produced in a further step, e.g., using the correspondinghydroxyalkyl derivative as starting material, in known manner.

The reaction step XXVI→XXVIII is conveniently effected by treating acompound of formula XXVI with an alkali metal alkoxide, preferably inthe presence of an inert solvent. Suitable solvents are hydrocarbons,e.g., hexane, toluene; ethers, e.g., tetrahydrofuran; dimethylformamide,dimethylsulfoxide, alcohols corresponding to the alkoxide used.Alternatively, a compound of formula XXVI is treated with an alkanol inthe presence of an organic base, e.g., pyridine or triethylamine. Thetemperature to be applied for this reaction step is preferably betweenabout -50° C. and the boiling point of the reaction mixture, mostpreferably between room temperature and about 100° C., with or withoutusing pressure above atmospheric pressure.

It is evident that a compound of formula XXVIII wherein R₁ is haloalkylhas to be produced in a further step as indicated above.

It is also evident that any hydroxyalkyl substituent present will haveto be protected during this reaction step and deprotected at a laterstage.

The reaction step XXVI→XXIX is conveniently effected by treating acompound of formula XXVI with an alkali cyanide, preferably in an inertsolvent. Suitable solvents are hydrocarbons, e.g., hexane, toluene;ethers, e.g., tetrahydrofuran; dimethylformamide, dimethylsulfoxide. Thetemperature for this reaction step is preferably situated between roomtemperature and the boiling point of the reaction mixture, mostpreferably between about 25° C. and 160° C.

It is evident that also in this step a compound of formula XXIX whereinR₁ is haloalkyl has to be produced in a further step as indicated above.

XXVI→XXVI'--Compounds of formula XXVI' are formed by reduction ofcompounds of formula XXVI with hydrogen using a suitable catalyst, e.g.,palladium or Raney nickel. This reaction step is conveniently effectedin the presence of an inert solvent. Suitable solvents are hydrocarbons,e.g., hexane, toluene; ethers, e.g., tetrahydrofuran, dioxane. Thereaction is preferably conducted at a temperature between about roomtemperature and the boiling point of the reaction mixture, mostpreferably at room temperature. If desired, pressure above atmosphericpressure can be applied.

It is evident that any nitro, cyano or additional haloalkyl substituentin a compound of formula XXVI' has to be formed at a later stage of thesynthesis.

XXV→XXX--Compounds of formula XXX are formed by reaction of formula XXV3-position aldehyde with an organometallic reagent such as a Grignardreagent or an alkyl lithium reagent. This reaction is convenientlyeffected in an inert solvent. Suitable solvents are hydrocarbons, e.g.,hexane, toluene; chlorinated hydrocarbons, e.g., methylene chloride,ethers, e.g., diethylether tetrahydrofuran, dimethoxyethane. Thereaction is preferably conducted at a temperature between about -100° C.and 50° C., most preferably between about -20° C. and room temperature.

It is evident that any carbonyl group in the substituent R₁ and R₄ hasto be protected during this reaction step. Since an ROOC-group would beaffected in the step XXV→XXX such a group has to be formed afterproduction of the compound of formula XXX, e.g., by using thecorresponding aldehyde with protected α-hydroxyalkyl substituent in the3-position as starting material. Further, any cyano substituent willhave to be formed at a later stage of the synthesis.

XVIII or XXII→XXXI--Compounds of formula XXXI may be produced by directaminolysis of formula XVIII (with an amino compound of the formula H₂ NRwhere R represents hydrogen, lower alkyl, lower alkenyl, aryl or thegroup --(CH₂)_(n) NR₁₃ R₁₄ wherein n is 1 to 4 and R₁₃, R₁₄ are definedabove) or by the conversion of a formula XXII compound to an acidchloride, e.g., by treatment with phosphorus pentachloride andsubsequent reaction with an amino compound of the formula HNRR' (whereinR, R' represent individually hydrogen, lower alkyl, hydroxy lower alkyl,lower alkenyl, aryl or form part of a heterocyclic ring or the group--(CH₂)_(n) NR₁₃ R₁₄ wherein n is 1 to 4 and R₁₃, R₁₄ are definedabove).

The step XVIII→XXXI is conveniently effected in an inert solvent or inthe absence of a solvent. Suitable solvents are hydrocarbons, e.g.,hexane, toluene; ethers, e.g., tetrahydrofuran; alcohols, e.g.,methanol, ethanol; dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide. It is preferable to perform this reaction step at atemperature between about 50° C. and 200° C., must be preferably betweenabout 100° C. and 150° C., applying atmospheric pressure of pressureabove atmospheric pressure.

It is evident that any haloalkyl or ROOC- substituent has to be formedsubsequent to production of the formula XXXI compound.

The step XXII→XXXI is conveniently effected in an inert solvent.Suitable solvents are hydrocarbons, e.g., hexane, toluene; ethers, e.g.,tetrahydrofuran, chlorinated hydrocarbons, e.g., methylene chloride,chlorobenzene. It is preferable to perform this reaction at atemperature between about -20° C. and the boiling point of the reactionmixture, most preferably between about 0° C. and 50° C.

It is evident that a hydroxyalkyl substituent has to be protected duringthis reaction step.

XXXI→XXXII--Formula XXXII compounds are formed by dehydration of formulaXXXI compounds where R and R' are hydrogen. Dehydration is accomplishedby reactants such as phosphorus pentoxide, phosphorusoxy chloride in acompatible solvent. Suitable solvents are pyridine, hydrocarbons, e.g.,hexane, toluene; chlorinated hydrocarbons, e.g., methylene chloride.Preferably this reaction is conducted at a temperature between roomtemperature and the boiling point of the reaction mixture, mostpreferably between about 50° C. and 120° C.

XVIII or XXII→XXXIV--Formula XXXIV compounds are formed by directhydrazinolysis or conversion to acid chloride, e.g., by treatment withphosphorous pentachloride, and subsequent treatment by a hydrazine. Thesymbols R¹⁰, R¹¹ and R¹² in formula XXXIV have the same meaning asindicated in formula I. The same reaction conditions as indicated forthe step XXII→XXXI can also be used for the step XXII→XXXIV and the samerestrictions as to substituents liable to being affected during thereaction should be observed. The reaction XVIII→XXXIV is convenientlyperformed in an inert solvent or in the absence of a solvent. Suitablesolvents are hydrocarbons, e.g., hexane, toluene; ethers, e.g.,tetrahydrofuran; alcohols, such as methanol, ethanol. Preferably thisreaction is conducted at a temperature between about 50° C. and 150° C.,most preferably between about 80° C. and 100° C. The same restrictionsas to substituents liable to be affected during this reaction stepshould be observed as indicated for the reaction step XVIII→XXXI.

XXII→XXXVI--Formula XXXVI compounds are formed by decarboxylation withor without catalyst and with or without solvent. This decarboxylation isconveniently effected by application of heat, e.g., at a temperaturebetween about 100° C. and 350° C., preferably about 150° C. and 230° C.Solvents that can be used in this reaction step are hydrocarbons, e.g.,mineral oil; chlorinated hydrocarbons, ethers, alcohols, e.g., ethyleneglycol, dimethylformamide, dimethylsulfoxide, hexamethyl phosphorictriamide. Useful catalysts are for instance metals such as copper powderor metal salts such as Cu⁺ or Ag⁺ salts.

XXII→XXXV--Formula XXXV compounds are formed by modified Curtiusreaction, i.e., by reaction of formula XXII compounds with phosphorylazides, e.g., N₃ PO(OC₆ H₅)₂, to form azides, i.e., formula XXXIIIcompounds, and subsequent heating of these azides with an alcohol whichtakes part in reaction. The azide formation is conveniently performed inan inert solvent. Suitable solvents are hydrocarbons, e.g., hexane,toluene; ethers, e.g., tetrahydrofuran. This reaction step is preferablyconducted at a temperature between about 0° C. and 100° C., preferablyat room temperature, if desired, utilizing pressure above atmosphericpressure although pressure is not critical. Preferred solvents includetriethylmine and pyridine.

It is obvious that any amino and substituted amino group present has tobe protected during this reaction step. It is also advisible to use acompound of formula XXII with protected hydroxyalkyl groups. Removal ofthe protecting group(s) can be effected after formation of compound offormula XXXV.

The conversion of the azide of formula XXXIII to the carbamic acid esterof formula XXXV, wherein R is lower alkyl or aralkyl, is convenientlyeffected in the alcohol reactant serving as solvent. Additionally, inertsolvents may be present such as hydrocarbons, e.g., hexane, toluene;chlorinated hydrocarbons, e.g., methylene chloride; ethers, e.g.,tetrahydrofuran; pyridine, triethylamine. Preferably the reaction isconducted at a temperature between about 50° C. and 200° C., mostpreferably between about 80° C. and 160° C.

It is evident that a haloalkyl substituent present would be affectedduring this reaction step and thus has to be formed subsequent to theproduction of compound of formula XXXV in known manner.

XXV→XXXVII--Formula XXXVII compounds are formed by reaction of formulaXXXV compounds where R is benzyl with palladium and hydrogen to yield afree amine which is acylated with an acid halide or acid anhydride. Theformation of the free amine is conveniently effected in an inertsolvent. Suitable solvents are hydrocarbons, e.g., hexane, toluene;ethers, e.g., tetrahydrofuran, alcohols, e.g., methanol, ethanol;organic acids, e.g., acetic acid, acid anhydrides, e.g., aceticanhydride, in which case the acylation occurs in situ. The preferredtemperature range for this reaction step is between room temperature andabove 100° C., if desired, using pressure above atmospheric pressure.For the acylation the same reaction conditions can be used as indicatedfor the step XXIII→XXIV.

It is evident that any haloalkyl, nitro and cyano substituents has to beformed subsequent to the production of the compound of formula XXXVII inknown manner. It is also evident that an amino group has to beprotected, e.g., in form of the corresponding phthalyl derivative.

XVIII'→XXXIX--Formula XXXIX compounds are formed by alkylation offormula XVIII' compounds wherein R₃ is hydrogen with alkyl halides inthe presence of strong base, e.g., methyl iodide in the presence ofpotassium tertiary butoxide. This reaction step is conveniently effectedin an inert solvent. Suitable solvents are hydrocarbons, e.g., hexane,toluene; ethers, e.g., tetrahydrofuran; dimethylformamide,dimethylsulfoxide. Preferably the reaction is conducted at a temperaturebetween about -50° C. and room temperature, most preferably betweenabout -30° C. and -10° C.

It is evident that any substituent present should not be a haloalkylsubstituent or a substituent with active hydrogen in case alkylation ofsuch latter substituent is undesirable.

XXX→XL--Formula XL (including XXV) compounds are formed by oxidation offormula XXX compounds as carried out in step XXIII→XXV (R is hydrogen orlower alkyl).

XL→XLI--Formula XLI compounds, wherein R is hydrogen or lower alkyl areformed by treatment of formula XL (including XXV) compounds with ahydrazine of formula NH₂ R', wherein R' is amino, mono- or dialkyl aminoor arylamino. This reaction is conveniently effected in an inertsolvent. Suitable solvents are hydrocarbons, e.g., hexane, toluene;chlorinated hydrocarbons, e.g., methylene chloride; ethers, e.g.tetrahydrofuran; alcohols, e.g., methanol, ethanol; organic acids, e.g.,acetic acid, pyridine. Preferably the reaction is conducted at atemperature between room temperature and the boiling point of thereaction mixture.

It is evident that any R₁ and/or R₄ acyl group has to be protectedduring this reaction step and that any haloalkyl group has to be formedsubsequent to the production of the compound of formula XLI.

XL→XLII--Formula XLII compounds wherein R' is hydrogen, hydroxy, loweralkyl or lower alkoxy and R is hydrogen or lower alkyl are formed byreaction of formula XL (including XXV) compounds with ammonia, hydroxylamine, a lower alkylamine or a lower alkoxyamine. This reaction step isconveniently effected in an inert solvent. Suitable solvents arehydrocarbons, e.g., hexane, toluene; chlorinated hydrocarbons, e.g.,methylene chloride; ethers, e.g., tetrahydrofuran; alcohols, e.g.,methanol, ethanol; organic acids, e.g., acetic acid; pyridine.Preferably the reaction is conducted at a temperature between roomtemperature and about 150° C., if desired, at a pressure aboveatmospheric pressure.

It is evident that any R₁ and/or R₄ acyl group has to be protectedduring this reaction step and that any haloalkyl group has to be formedsubsequent to the production of the compound of formula XLII.

XLI or XLII→XLIII--Formula XLIII compounds, wherein R is hydrogen orlower alkyl are obtained by reduction of formula XLI or XLII compoundse.g. utilizing Raney nickel and hydrogen. This reaction step isconveniently effected in an inert solvent. Suitable solvents arehydrocarbons, e.g., hexane, toluene; ethers, e.g., tetrahydrofuran;alcohols, e.g., methanol, ethanol; dimethylformamide; organic acids,e.g., acetic acid; organic acid anhydrides, e.g., acetic acid anhydride,in which case acylation at the amino group formed occurs in situ leadingto an acylated compound of formula XLIII. It is preferable to conductthis reaction step at a temperature between about 0° C. and 100° C.,most preferably at room temperature, if desired, applying pressure aboveatmospheric pressure.

It is evident that any haloalkyl, nitro and cyano group has to be formedsubsequent to the production of the compound of formula XLIII.

XXXVI→XLIV--Formula XLIV compounds wherein X is chloro, bromo or iodoare obtained by reacting formula XXXVI compounds wherein R₂ is hydrogenwith an appropriate halogenating agent such as bromine,N-bromosuccinimide, N-chlorosuccinimide, etc. This reaction step isconveniently effected in an inert solvent. Suitable solvents arehydrocarbons, e.g., hexane, toluene; chlorinated hydrocarbons, e.g.,methylene chloride; organic acids, e.g., acetic acid, inorganic acids,e.g., sulfuric acid. Preferably the reaction is conducted at atemperature between about 0° C. and the boiling point of the reactionmixture depending on the reagent used.

It is evident that any hydroxyalkyl and aminoalkyl substituent presentmust be protected during this reaction step. Furthermore the meaning ofR₁ must be other than hydrogen. A compound of formula XLIV wherein R₁ ishydrogen can be produced from a corresponding compound wherein R₁ is--COOR by means of saponification and subsequent decarboxylation.

XXXVI→XLV→XLVI--Formula XLV compounds wherein R₂ is hydrogen, loweralkyl, lower alkoxy alkyl or acyloxy lower alkyl are obtained byreacting corresponding formula XXXVI compounds with a peracid such asmeta chloro perbenzoic acid or peracetic acid. In the instances where R₁is lower alkyl and R₂ is hydrogen, a compound of the formula XLVI isformed by subsequent reaction with an acid anhydride. The symbol A informulae XLV and XLVI stand for the group --C(R₆)═N-- and--C(R₆)═N(→O)-- and R in formulae XLVI, XLVIII and XLVII is hydrogen orlower alkyl. The reaction step XXXVI→XLV is conveniently effected in aninert solvent. Suitable solvents are hydrocarbons, e.g., hexane,toluene; chlorinated hydrocarbons, e.g., methylene chloride; organicacids, e.g., acetic acid. Preferably the reaction is conducted at atemperature between about 0° C. and 50° C.

It is evident that any acyl group and preferably also any hydroxyalkylgroup present should be protected during this reaction step.Furthermore, the presence of tertiary amino groups, ROOC-groups as wellas ##STR93## representing pyrazolo and R₆ representing pyridyl isexcluded for this reaction step. An acyloxy alkyl group present may betransformed into a hydroxyalkyl, a haloalkyl, an aminoalkyl, asubstituted aminoalkyl or a cyanoalkyl group subsequent to the formationof the compound of formula XLV.

The treatment with an acid anhydride, e.g., acetic acid anhydride forthe conversion XLV→XLVI is conveniently effected in an inert solvent.Suitable solvents are hydrocarbons, e.g., hexane, toluene; chlorinatedhydrocarbons, e.g., methylene chloride; ethers, e.g., tetrahydrofuran;dimethylformamide; dimethylsulfoxide. Acid anhydrides taking part in thereaction can also be used as solvents. This reaction step isadvantageously effected at a temperature between room temperature andabout 150° C., preferably between about 80° C. and 100° C.

It is evident that any amino group present will be acylated and anyhydroxyalkyl group present will be esterified during this reaction step.

XLVI→XLVIII--Formula XLVIII compounds wherein A is as in formula XLV areobtained by reacting corresponding formula XLVI compounds with an alkalimetal alkoxide or hydroxide. This reaction step is conveniently effectedin an inert solvent. Suitable solvents are hydrocarbons, e.g., hexane,toluene; chlorinated hydrocarbons, e.g., methylene chloride; ethers,e.g., tetrahydrofuran; alcohols, e.g., methanol, ethanol;dimethylformamide; dimethylsulfoxide; hexamethyl phosphoric triamide;pyridine, amines, e.g., triethylamine. This reaction is preferablyconducted at a temperature between about 0° C. and the boiling point ofthe reaction mixture depending on the reagent used.

XLVIII→XLVII--Formula XLVII compounds wherein A is as in formula XLV areformed by oxidation as in step XXIII→XXV.

XIII'→LV--Compounds of the formula LV are prepared by reacting a formulaXIII' compound with a nitrone anion formed by the reaction of a formulaLVI compound wherein R₁ ' is phenyl, substituted phenyl or pyridyl and Ris lower alkoxy or di-lower alkyl amino with a strong base, such as,butyl lithium, potassium tertiary butoxide, etc. The reaction (XIII'→LV)is effected in situ without isolation of intermediate compounds such asLIII and LIV. Solvents suitable for this reaction include hydrocarbonssuch as hexane, toluene, etc., ethers, e.g., THF, DMF and DMSO. Reactiontemperature should be in the range of -100° C. to room temperature,preferably -80° C. to 25° C. e.g., about -70° C. with subsequent warmingto room temperature to effect in situ cyclization.

XLIX (XXXIV')→L--Compounds of formula L are formed by reaction offormula XLIX compounds with nitrous acid to the azide. Solvents for thisreaction include chlorinated hydrocarbons, alcohols such as methanol,ethanol, etc., organic acids, water and aqueous inorganic acids. Thetemperature at which the reaction is carried on can vary between -20° C.to room temperature with 0° C. to room temperature being preferred.

L→LII--Formula LII compounds are formed by the reaction of a formula Lcompound as disclosed in step XXII→XXXV utilizing the reactionparometers set forth.

LII→LI--Formula LI compounds are formed by reduction of formula LIIcompounds using Raney nickel and hydrogen. Solvents includehydrocarbons, e.g., hexane, toluene, benzene; ethers, e.g., THF andDMSO; alcohols, e.g., methanol, ethanol, etc., and organic acids. Thereaction temperature ranges from 0° C. to 50° C. with room temperaturebeing preferred. The reaction may be run, with or without theutilization of pressure.

Homologs of compounds of formulae XXVII, XXIX, XXIV, XXVI, XXVIII andXXVI' and compounds of formula XXX where the functional group in thesubstituent R₂ is in another position than the α-position can beprepared by homologation and/or modification of appropriate compoundsdisclosed above. For instance compounds of formula XXIX can be convertedto the corresponding ester which in term can be subjected to similarreactions as disclosed above for the conversion of compounds of formulaXVIII.

Compounds of the formulae I, IA, IB, IC, ID and IE and theirpharmaceutically acceptable acid addition salts are useful as musclerelaxants, sedatives and anticonvulsants and many are particularlyuseful when utilized in intravenous and intramuscular preparationsbecause of the acid addition salts' solubility in aqueous solution. Ascontemplated by this invention, the novel compounds of the formula I andtheir acid addition salts can be embodied in pharmaceutical dosageformulations containing from about 0.1 to about 40 mgs. most preferably1-40 mg with dosage adjusted to species and individual requirements. Thenovel compounds of formulae I, IA, IB, IC, ID and IE and theirpharmaceutically acceptable salts can be administered internally, forexample, parenterally or enterally, in conventional pharmaceuticaldosage forms. For example, they can be incorporated in conventionalliquid or solid vehicles such as water, gelatin, starch, magnesiumstearate, talc, vegetable oils and the like to provide tablets, elixirs,capsules, solutions, emulsions and the like according to acceptablepharmaceutical practices.

Applicants, in setting forth the disclosure of the above specificationhave cited the teaching of various articles and U.S. Patents. Suchcitations are meant to incorporate the teachings of these references forcompleteness of disclosure.

The following examples are illustrative but not limitative of thepresent invention. All temperatures are stated in degrees Centigrade.

EXAMPLE 17-Chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine

A solution of 200 g. (0.695 m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 2l. of tetrahydrofuran and 250 ml. of benzene was saturated withmethylamine with cooling in an ice bath. A solution of 190 g. (1 m) oftitaniumtetrachloride in 250 ml. of benzene was added through a droppingfunnel within 15 minutes. After addition the mixture was stirred andrefluxed for 3 hours. Water, 600 ml., was added slowly to the cooledreaction mixture. The inorganic material was separated by filtration andwas washed well with tetrahydrofuran. The water layer was separated andthe organic phase was dried over sodiumsulfate and evaporated. Thecrystalline residue was collected with m.p. 204°-206°. The analyticalsample was recrystallized from methylene chloride/ethanol, m.p.204°-206°.

EXAMPLE 27-Chloro-5-(2-chlorophenyl)-2-methylamino-3H-1,4-benzodiazepine

Reaction as in Example 1 of 152.5 g. (0.5 m) of7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-onesaturated with methylamine with 133 g. (0.7 m) of titaniumtetrachloridein 2 l. of tetrahydrofuran and 400 ml. of benzene yielded product withm.p. 216°-219°. The analytical sample was recrystallized from methylenechloride/ethanol and had m.p. 217°-219°.

EXAMPLE 3 5-(2-Chlorophenyl)-7-nitro-2-methylamino-3H-1,4-benzodiazepine

A solution of 94.6 g. (0.3 m) of5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one in 2l. of tetrahydrofuran and 300 ml. of benzene was cooled in ice-water andsaturated with methylamine. A solution of 40.2 ml. (0.36 m) oftitaniumtetrachloride in 300 ml. of benzene was added through a droppingfunnel. After addition the mixture was stirred and refluxed for 3 hours.Water, 300 ml., was added slowly to the cooled reaction mixture. Theinorganic solids were separated by filtration and washed well withtetrahydrofuran. The water was separated from the filtrate and theorganic phase was dried over sodiumsulfate and evaporated. The residuewas chromatographed over 500 g. of silica gel using 10% (v/v) ethanol inmethylene chloride. Crystallization of the clean fractions frommethylene chloride/ethanol yielded a yellow product with m.p. 219°-221°.

EXAMPLE 45-(2-Chlorophenyl)-7-nitro-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine

Sodium nitrite, 8.63 g. (0.125 m), was added in three portions over a 15minute period to a solution of 33.9 g. (0.1 m) of5-(2-chlorophenyl)-7-nitro-2-methylamino-3H-1,4-benzodiazepine in 200ml. of glacial acetic acid. After addition stirring was continued for11/2 hours at room temperature and the product was precipitated byaddition of water. The yellow solids were collected, washed with water,sucked dry and recrystallized from ethanol to yield yellow crystals withm.p. 164°-166°. The analytical sample was recrystallized from methylenechloride/ethanol, m.p. 167°-169°.

EXAMPLE 57-Chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine4-oxide

A solution of 33 g. (0.1 m) of7-chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxidein 100 ml. of dimethylformamide was added to a mixture of 50 ml. ofnitromethane, 12.5 g. (0.11 m) of potassium t-butoxide and 100 ml. ofdimethylformamide. The reaction mixture was stirred under a stream ofnitrogen for 1 hour. Afer addition of 10 ml. of glacial acetic acid, theproduct was crystallized by gradual addition of 250 ml. of water. Theprecipitated yellow material was collected, washed with water, methanoland ether to leave material with m.p. 253°-255° dec. The analyticalsample was recrystallized from methylene chloride and showed the samem.p.

EXAMPLE 67-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine

A mixture of3.3 g. (0.01 m) of7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine4-oxide, 3.3 ml. of phosphorus trichloride and 300 ml. of methylenechloride was stirred at room temperature for 4 hours. The solution waswashed with 10% aqueous sodium carbonate solution, was dried over sodiumsulfate and evaporated. The crude product was purified by chromatographyover 100 g. of silica gel using 10% (v/v) ethyl acetate in methylenechloride. The combined clean fractions were crystallized from methylenechloride/hexane to yield light yellow crystals with m.p. 184°-186°.

EXAMPLE 77-Chloro-5(2-chlorophenyl)-1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine

Sodium nitrite, 10 g. (0.145 m), was added in portions over 45 minutesto a solution of 22.4 g. (0.07 m) of7-chloro-5-(2-chlorophenyl)-2-methylamine-3H-1,4-benzodiazepin in 150ml. of glacial acetic acid. After addition stirring was continued for 20minutes under nitrogen. The product was precipitated by addition ofice-water, collected and dissolved in toluene. The solution was washedwith saturated aqueous sodium bicarbonate, dried and evaporated underreduced pressure. The yellow viscous oil (24 g.) consisted according tothin layer chromatogram mainly of the desired nitrosoamidine. Thismaterial was dissolved in 100 ml. of dimethylformamide and was added toa mixture of 30 ml. of nitromethane, 100 ml. of dimethylformamide and 10g. of potassium t-butoxide. The reaction mixture was slowly heated up to85° with stirring under a nitrogen stream. After 5 minutes, the reactionmixture was cooled, acidified by addition of 10 ml. of glacial aceticacid. The product was crystallized by gradual addition of water withseeding (seeds were obtained by chromatography over silica gel using 10%ethyl acetate in methylene chloride). The separated crystals werecollected, washed with water and recrystallized from methylenechloride/ethanol to yield product with m.p. 182°-185°.

EXAMPLE 87-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine

Sodium nitrite, 8.63 g. (0.125 m), was added in three portions over a 15minute period to a solution of 30.15 g. (0.1 m) of7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine in 150ml. of glacial acetic acid. After stirring for 1 hour at roomtemperature the reaction mixture was diluted with water and extractedwith methylene chloride. The extracts were washed with saturated sodiumbicarbonate solution, were dried over sodium sulfate and evaporated, atthe end azeotropically with toluene to yield 29 g. of crude7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepineas a yellow oil.

This material was dissolved in 100 ml. of dimethylformamide and added toa mixture of 200 ml. of dimethylformamide, 50 ml. of nitromethane and11.1 g. (0.1 m) of potassium t-butoxide which had been stirred undernitrogen for 15 minutes.

After stirring for 1 hour at room temperature, the reaction mixture wasacidified by addition of glacial acetic acid, was diluted with water andextracted with methylene chloride. The extracts were washed with water,dried over sodium sulfate and evaporated.

Crystallization of the residue from ether yielded product with m.p.170°-172°. The analytical sample was recrystallized from methylenechloride/ethanol, m.p. 174°-176°.

EXAMPLE 97-Bromo-1,3-dihydro-2-nitromethylene-5-(2-pyridyl)-2H-1,4-benzodiazepine

A mixture of 3.6 g. (0.01 m) of7-bromo-2-(N-nitrosomethylamino)-5-(2-pyridyl)-3H-1,4-benzodiazepine, 30ml. of dimethylformamide, 5 ml. of nitromethane and 2 g. (0.018 m) ofpotassium t-butoxide was stirred at room temperature for 15 minutes andthen heated up slowly. When the temperature reached 100° the mixture wascooled and neutralized by addition of glacial acetic acid. The productwas precipitated by addition of saturated aqueous sodium bicarbonate andwas coolected, washed with water and dissolved in methylene chloride.The solution was dried over sodium sulfate and evaporated.Crystallization of the residue from methylene chloride/ethanol yielded alight yellow product with m.p. 232°-235° dec. For analysis it wasrecrystallized from tetrahydrofuran/ethanol, m.p. 240°-245° dec.

EXAMPLE 105-(2-Chlorophenyl)1,3-dihydro-7-nitro-2-nitromethylene-2H-1,4-benzodiazepine

A mixture of 3.58 g. (0.01 m) of5-(2-chlorophenyl)-7-nitro-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine,20 ml. of dimethylformamide, 5 ml. of nitromethane and 1.3 g. (0.0115 m)of potassium t-butoxide was stirred at room temperature for 15 minutesunder nitrogen. After addition of 2 ml of glacial acetic acid thereaction mixture was partitioned between methylene chloride and water.The organic phase was washed with water, dried over sodium sulfate andevaporated. The residue was chromatographed over 80 g. of silica gelusing 10% (v/v) ethyl acetate in methylene chloride. Crystallization ofthe clean fractions from methylene chloride/ethanol yielded strawcolored crystals with m.p. 240°-243° dec.

EXAMPLE 118-Chloro-3a,4-dihydro-1-methyl-6-phenyl-3H-imidazo[1,5-a][1,4]benzodiazepine

Raney nickel (5 teaspoons) was added to a solution of 16.5 g. (0.05 m)of 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine4-oxide, in 500 ml. of tetrahydrofuran and 250 ml. of methanol. Themixture was hydrogenated for 5 hours at atmospheric pressure. Thecatalyst was removed by filtration and the filtrate was evaporated. Theresidue was dissolved in 2-propanol and the solution was made stronglyacidic with ethanolic hydrogen chloride. The dihydrochloride of theproduct crystallized upon evaporation of part of the solvent. The orangecrystals were collected to leave2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepinedihydrochloride with m.p. 230°-240°.

Acetic anhydride, 10 ml. was added to a solution of 10 g. of the abovehydrochloride in 50 ml. of water and 50 ml. of methanol. A 10% aqueoussolution of sodium carbonate, 100 ml., was added with stirring over aperiod of 5 minutes. After addition the mixture was stirred for anadditional ten minutes and was then extracted with methylene chloride.The extracts were washed with sodium carbonate solution, dried oversodium sulfate and evaporated, at the end azeotropically with toluene.2-Acetaminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepinewas obtained as a yellow resin.

The above material was heated in 50 g. of polyphosphoric acid to135°-140° for 10 minutes. The initially orange color of the reactionmixture faded to a light yellow. The cooled reaction mixture wasdissolved in water, made alkaline with concentrated ammonia and ice andextracted with methylene chloride. The extracts were dried andevaporated. The yellow resin was dissolved in 2-propanol and treatedwith ethanolic hydrogen chloride whereupon the colorless dihydrochlorideof the product crystallized. Melting point was 240°-245°.

This hydrochloride was partitioned between methylene chloride andaqueous ammonia. The organic phase was dried and evaporated.Crystallization of the residue from ether yielded a colorless productwith m.p. 116°-118°.

EXAMPLE 128-Chloro-3a,4-dihydro-1-ethyl-6-(2-fluorophenyl)-3H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 16.5 g. (0.05 m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepinein 500 ml. of tetrahydrofuran and 250 ml. of methanol was hydrogenatedwith 5 teaspoons of Raney nickel for 21/2 hours at atmospheric pressure.Separation of the catalyst and evaporation left 14 g. of crude2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine.

Propionic anhydride, 20 ml., was added to a solution of 12 g. of thismaterial in 300 ml. of methylene chloride. The solution was layered with300 ml. of 10% aqueous sodium carbonate solution and the two phasemixture was stirred at room temperature for 30 minutes. The organiclayer was separated, washed with sodium carbonate solution and driedover sodium sulfate. Evaporation yielded crude7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-propionylaminomethyl-1H-1,4-benzodiazepine.

This material was heated in 50 g. of polyphosphoric acid at 150°-170°for 10 minutes. The reaction mixture was cooled, dissolved in water andmade alkaline with concentrated ammonia and ice. The base was extractedwith methylene chloride and the extracts were dried over sodium sulfateand evaporated. The residue was chromatographed over 300 g. of silicagel using 20% methanol in methylene chloride. The clean fractions werecombined, evaporated and the residue was crystallized from ether toyield a product with m.p. 131°-133°.

EXAMPLE 138-Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 3.1 g. (0.01 m) of8-chloro-3a,4-dihydro-1-methyl-6-phenyl-3H-imidazo[1,5-a][1,4]benzodiazepine,20 g. of activated manganese dioxide and 150 ml. of toluene was refluxedfor 1 hour. The manganese dioxide was removed by filtration over celiteand was washed well with methylene chloride. The filtrate was evaporatedand the residue was crystallized from ether to yield colorless crystalswith m.p. 187°-188°.

EXAMPLE 148-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Acetic anhydride, 7 ml., was added to a solution of 6.16 g. of crude2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinein 200 ml. of methylene chloride. The solution was layered with 200 ml.of saturated aqueous sodium bicarbonate and the mixture was stirred for20 minutes. The organic layer was separated, washed with sodiumbicarbonate, dried over sodium sulfate and evaporated to leave 6.2 g.resinous2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine.This material was heated with 40 g. of polyphosphoric acid at 150° for10 minutes. The cooled reaction mixture was dissolved in water, madealkaline with ammonia and ice and extracted with methylene chloride. Theextracts were dried and evaporated and the residue (5.7 g.) waschromatographed over 120 g. of silica gel using 20% methanol inmethylene chloride. The clean fractions were combined and evaporated toyield resinous8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine. A mixture of this material with 500 ml. oftoluene and 30 g. of manganese dioxide was heated to reflux for 11/2hours. The manganese dioxide was separated by filtration over celite.The filtrate was evaporated and the residue was crystallized from etherto yield a product with m.p. 152°-154°. The analytical sample wasrecrystallized from methylene chloride/hexane.

EXAMPLE 158-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Hydrogenation of 7 g. of7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepinein 300 ml. of tetrahydrofuran and 150 ml. of methanol in the presence ofRaney nickel (5 teaspoonsful) for 1 hour yielded crude2-aminomethyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine.This material was acetylated in the usual fashion to leave oily2-acetaminomethyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepinewhich was heated in 15 g. of polyphosphoric acid for 10 minutes at140°-150°. The usual workup afforded a yellow resin which waschromatographed over 250 g. of silica gel using 20% methanol inmethylene chloride.

The clean fractions left 1.3 g. of resinous8-chloro-6-(2-chlorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.This material was oxidized with 10 g. of manganese dioxide in 200 ml. oftoluene. After heating to reflux for 11/2 hour, the manganese dioxidewas separated and the filtrate was evaporated. Crystallization of theresidue from ether yielded a product with m.p. 140°-144° . For analysisit was recrystallized from methylene chloride/hexane, m.p. 142°-144°.

EXAMPLE 168-Chloro-1-ethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 3.4 g. of8-chloro-3a,4-dihydro-1-ethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine,400 ml. toluene and 30 g. activated manganese dioxide was refluxed withseparation of water in a Dean-Stark trap for 2 hours. The manganesedioxide was separated by filtration over celite and the filtrate wasevaporated. Crystallization of the residue from ether yielded a productwith m.p. 140°-143°. For analysis it was recrystallized from ether, m.p.143°-145°.

EXAMPLE 177-Chloro-1,3-dihydro-5-(2-fluorophenyl-2-(1-nitroethylene)-2H-1,4-benzodiazepine

A mixture of 11.2 g (0.1 m) of potassium tert. butoxide, 50 ml ofnitroethane and 200 ml of dimethylformamide was stirred at roomtemperature for 15 min. A solution of 29 g (0.088 m) of crude7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepinein 100 ml of dimethylformamide was then added and stirring undernitrogen was continued for 6 hrs. The reaction mixture was neutralizedby addition of glacial acetic acid and diluted with water. The productwas extracted with ether. The extracts were washed with saturatedaqueous sodiumbicarbonate solution, dried over sodium sulfate andevaporated. Crystallization from ether yielded a final product as yellowcrystals with mp 136°-142°.

EXAMPLE 188-Chloro-1,3-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepineand8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

Raney nickel, 5 teaspoonsful, was added to a solution of 17.3 g (0.05 m)of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-(1-nitroethylene)-2H-1,4-benzodiazepinein 750 ml of tetrahydrofuran. The mixture was hydrogenated atatmospheric pressure for 4 hrs. The catalyst was removed by filtrationover celite and was washed well with methanol. The filtrate wasevaporated to leave crude2-(1-aminoethyl)-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepineas a reddish oil. This material was dissolved in 300 ml of methylenechloride. Following the addition of 14 ml of acetic anhydride, 300 ml ofsaturated aqueous sodium bicarbonate solution was added and thetwo-phase mixture was stirred at room temperature for 1 hr. Themethylene chloride layer was separated, washed with bicarbonate, driedover sodium sulfate and evaporated. The residue, 13.5 g, was heated with40 g of polyphosphoric acid for 10 minutes at 160°-170°. The coolreaction mixture was diluted with water, made alkaline with ammonia andextracted with methylene chloride. The extracts were washed with water,dried and evaporated to leave 11 g of a brown residue which waschromatographed on 250 g of silica gel using 20% (v/v) methanol inmethylene chloride. The thin layer chromatographically homogeneousfractions were combined to yield a resin which was subjected to thefollowing oxidation.

A mixture of the above material, 20 g of activated manganese dioxide and300 ml of toluene was heated to reflux for 3 hrs using a Dean-Stark trapto remove the water. The manganese dioxide was separated by filtrationover celite and was washed well with methylene chloride. The filtratewas evaporated and the residue, 4.2 g, was chromatographed with pressureover 150 g of silica gel H using 3% ethanol in methylene chloride. Thefirst eluted major component was8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine.

It was converted to a crystalline dihydrochloride by treatment withethanolic hydrogen chloride in ether. Mp 247°-250° dec.

The more polar component could be crystallized from methylenechloride/ether/hexane to yield8-chloro-1,3-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinewith mp. 178°-180°.

EXAMPLE 198-Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxide

A mixture of 3.1 g (0.01 m) of8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine, 2.15 g(0.0125 m) of m-chloroperbenzoic acid and 100 ml of methylene chloridewas stirred for 48 hrs. at room temperature. It was then washed with 10%aqueous sodium carbonate solution and water. The methylene chloridelayer was dried over sodium sulfate and evaporated. The residue waschromatographed over 80 g of silica gel using 10% (v/v) of ethanol inmethylene chloride. The Tlc-homogeneous fractions were combined andevaporated. Crystallization of the residue from methylene chloride/etheryielded a final product with mp 260°-261°.

EXAMPLE 204-Acetoxy-8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 1 g of8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxidein 20 ml of acetic anhydride was heated on the steam bath for 24 hrs.The reagent was evaporated under reduced pressure and the residue wascrystallized from ether to yield a final product with mp 200°-201°.

EXAMPLE 218-Chloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Sodium methoxide, 0.54 g, was added to a solution of 0.73 g (2 mmol) of4-acetoxy-8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 20 ml of methanol. After sitting at room temperature for 30 min, thesolvent was evaporated under reduced pressure after neutralization withacetic acid. The residue was partitioned between methylene chloride andsodium bicarbonate solution. The organic layer was dried over sodiumsulfate and evaporated. Crystallization of the residue from etheryielded a final product with mp 173°-174°.

EXAMPLE 228-Choro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate

A warm solution of 6.5 g (0.02 m) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 m)of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 mlof ether and heated on the steam bath for 3 min. After cooling, thecrystals were collected, washed with ether and dried in vacuo to yield afinal product with mp 148°-151°.

EXAMPLE 23

A mixture of 17.4 g (0.05 m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-(1-nitromethylene)-2H-1,4-benzodiazepine4-oxide, 500 ml of tetrahydrofuran, 200 ml of methanol and 5 teaspoonfulof Raney nickel was hydrogenated at atmospheric pressure for 5 hrs. Thecatalyst was removed by filtration and the filtrate was evaporated atthe end azeotropically with xylene to leave crude2-aminomethyl-7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine.

This material was dissolved in 200 ml of ethanol and the solution washeated to reflux for 2 hrs. after addition of 14 ml oftriethylorthoacetate and 2.8 g of p-toluenesulfonic acid. The solventwas evaporated under reduced pressure and the residue was partitionedbetween methylene chloride and 10% aqueous sodium carbonate solution.The organic layer was dried and evaporated to yield oily8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine.This crude product was dissolved in 500 ml of xylene. After addition of50 g of activated manganese dioxide, the mixture was stirred and heatedto reflux for 11/2 hrs with separation of water in a Dean-Stark trap.The inorganic material was removed by filtration and the filtrate wasevaporated to leave 10 g of brown oil.

A warm solution of 4.65 g (0.04 m) of maleic acid in 50 ml of ethanolwas added to this residue. After the solution was complete, the productwas crystallized by addition of ether. It was collected and washed withether to leave the maleate of Example 22 with mp 112°-115°. Heatingunder vacuum at 90° to 100° converts this product to the higher meltingform, i.e. M.P.=148°-151°.

EXAMPLE 248-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinedihydrochloride

A solution of 0.32 g (1 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 5 ml of ethanol was treated with excess ethanolic hydrogen chloride.The salt was crystallized by addition of 2-propanol and ether. Thecolorless crystals were collected, washed with ether and dried to leavea final product with mp 290°-295°.

EXAMPLE 258-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinehydrochloride

A solution of 0.325 g (1 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 3 ml of ethanol was combined with a suspension of 0.4 g (1 mmol) ofthe dihydrochloride of this compound in 5 ml of ethanol. Afterfiltration, the solution was treated with ether and heated on thesteambath for 5 min to crystallize. The crystals were collected, washedwith ether and dried to leave the monohydrochloride with mp 295°-297°.

EXAMPLE 26 1,3-Dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine

To a cooled (10°), stirred solution of 10.0 g (0.04 m) of2-methylamino-5-phenyl-3H-1,4-benzodiazepine in 100 ml of pyridine wasadded 100 ml of a saturated solution of nitrosyl chloride in aceticanhydride. The solution was stirred for 3.5 hr. during which time it wasallowed to warm to ambient temperature. The solution was poured into 300ml of ice-water, and the aqueous solution was extracted with five 150-mlportions of methylene chloride. The combined organic extracts werewashed with water and brine, dried (CaSO₄), and the solvent removedunder reduced pressure affording 11.7 g of a dark semi-solid.Chromatography on 500 g of silica gel (chloroform elution) afforded the2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine, mp 192°-199°dec. This material was used in the following step:

The conjugate base of nitromethane was prepared by treatment of 50 ml ofnitromethane in 200 ml of DMF with 5.7 g (0.05 m) of potassiumtert-butoxide. The resultant stirred yellow suspension was treated with10.9 g of crude 2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepinein 100 ml of DMF. The dark mixture thus obtained was stirred for 2 hrs.at 25° and for 1 hr at 85° and then cooled to 25° and poured onto 1 l.of water. After acidification with acetic acid, the aqueous solution wasextracted with four 250-ml portions of methylene chloride, and thecombined organic extracts were then washed with water and brine, dried(CaSO₄), and concentrated in vacuo to give a dark oil which was purifiedby chromatography over 1 kg. of silica gel (CHCl₃ elution) to affordcrude product, mp 131°-142°.

An analytical sample, mp 141°-142°, was prepared by recrystallizationfrom ethanol.

EXAMPLE 27 1-Methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 8.4 g (0.03 m) of1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine, 75 ml oftetrahydrofuran, 75 ml of methanol and 2 teaspoonsful of Raney nickelwas hydrogenated at atmospheric pressure for 6 hrs. The catalyst wasremoved by filtration and the filtrate was evaporated to leave crude2-aminomethyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine.

This material was dissolved in 50 ml of methylene chloride and wastreated with 6 ml of acetic anhydride and 200 ml of saturated aqueoussodium bicarbonate solution for 15 min. with stirring. The methylenechloride layer was separated, washed with bicarbonate solution, driedand evaporated. The residue was treated with 25 g of polyphosphoric acidto 130°-150° for 15 min. The cooled reaction mixture was partitionedbetween water and ether. The aqueous phase was made alkaline withammonia and was extracted with methylene chloride. The extracts weredried and evaporated. Chromatography of the residue over 70 g of silicagel with 20% (v/v) ethanol in methylene chloride yielded 3a,4-dihydro-1-methyl-6-phenyl-3H-imidazo[1,5-a][1,4]benzodiazepine as alight yellow resin.

This material was heated in 50 ml of toluene with 7 g of activatedmanganese dioxide to reflux for 11/2 hrs. The inorganic material wasfiltered off and the filtrate was evaporated. The residue was purifiedby chromatography over 30 g of silica gel using 10% ethanol in methylenechloride. The clean fractions were combined and evaporated.Crystallization of the residue from ether yielded a final product withmp 180°-182°.

EXAMPLE 282-Aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinedimaleate

A suspension of 17 g (0.05 m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxidein 200 ml of tetrahydrofuran and 100 ml of methanol was hydrogenated inpresence of 17 g of Raney nickel at an initial pressure of 155 psi for24 hrs. The catalyst was removed by filtration and the filtrate wasevaporated. The residue was dissolved in 50 ml of 2-propanol and warmedon the steambath. A warm solution of 17 g of maleic acid in 60 ml ofethanol was added and the salt was allowed to crystallize by cooling inthe ice bath. The final product consisted of yellow crystals with mp196°-198°.

EXAMPLE 297-Chloro-2-di-(morpholino)-phosphinyloxy-5-(2-fluorophenyl)-3-methyl-3H-1,4-benzodiazepine

To a stirred solution of 6 g. (0.02 m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2H-1,4-benzodiazepin-2-onein 100 ml of dry tetrahydrofuran was added 1.05 g, (0.25 m) of 57%sodium hydride dispersion in mineral oil. The mixture was placed underargon and refluxed for 1 hr. After cooling to room temperature, themixture was treated with 7.4 g (0.03 m) of dimorpholinophosphinicchloride and stirring under argon was continued at room temperature for2 hrs. The mixture was filtered and evaporated at reduced pressure togive a gummy residue. Stirring the gum with 100 ml of anhydrous ethergave white crystals which were collected by filtration, washed with alittle ether and air dried. The final product had a m.p. of 90°-95°.

EXAMPLE 30 7-Chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiazepine

A stirred solution of 2.4 g (0.04 m) of nitromethane in 50 ml of drydimethylformamide was treated with 1 g (0.024 m) of 57% sodium hydridedispersion in mineral oil at room temperature under argon. Afterstirring for 1 hr. at room temperature, the mixture was treated with 5.2g (0.01 m) of7-chloro-2-di(-morpholino)-phosphinyloxy-5-(2-fluorophenyl)-3-methyl-3H-1,4-benzodiazepinein one portion and stirring under argon was continued at roomtemperature for 24 hrs. The dark mixture was poured over a mixture ofice and glacial acetic acid with stirring to give a yellow solid.Stirring was continued until the ice had melted. The solid was filtered,washed with water and air dried on the funnel to yield a product havingmp of 215° dec. Recrystallization of a sample from 1:1 methanolmethylenechloride solution gave yellow needles, mp 219°-221° dec.

EXAMPLE 318-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepineDihydrochloride

A solution of 5.2 g (0.015 m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiazepinein 450 ml of 2:1 tetrahydrofuran-methanol was hydrogenated for 3 hrs.using a Parr apparatus, Raney nickel catalyst (3 teaspoonsful) and aninitial pressure of 18 psi. The mixture was filtered and evaporated atreduced pressure to give crude2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-methyl-1H-1,4-benzodiazepineas a yellow oil.

The crude aminomethyl compound was mixed with 5 ml of triethylorthoacetate, and 0.5 g of p-toluenesulfonic acid monohydrate in 100 mlof ethanol. After heating under reflux for 2 hrs, the solution wasevaporated at reduced pressure. The residue was cooled to roomtemperature, treated with a mixture of ice and concentrated ammoniumhydroxide and extracted with methylenechloride. Evaporation of the driedextracts in vacuo gave crude8-chloro-3a,4-dihydro-1,4-dimethyl-6-(2-fluorophenyl)-3H-imidazo[1,5-a][1,4]benzodiazepineas a gum.

The crude dihydroimidazobenzodiazepine was mixed with 20 g of activatedmanganese dioxide and 200 ml of toluene and heated under reflux for 2hrs. The mixture was filtered and the manganese dioxide was washed withmethylene chloride. Evaporation of the combined filtrate and washings atreduced pressure gave a brown gum. The dihydrochloride of the productwas obtained as a white powder by stirring the gum with ethanolichydrogen chloride for a few minutes. The salt melted at 247°-250°.

EXAMPLE 328-Chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Zinc dust, 3 g, was added to a solution of 2.8 g of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 75 ml of methylene chloride and 75 ml of glacial acetic acid. Afterstirring at room temperature for 2 hrs, the inorganic material wasfiltered off and washed with methylene chloride and water.

The filtrate was diluted with 100 ml of methylene chloride and 200 ml ofwater and was made alkaline with ammonia. The methylene chloride layerwas separated, dried and evaporated. Crystallization of the residue fromether/hexane yielded a final product with mp 200°-203°.

EXAMPLE 336-Chloro-2-(1,1-dichloroethyl)-1,2-dihydro-4-(2-fluorophenyl)quinazoline3-oxide

A mixture of 49.9 (0.2 moles) of 2-amino-5-chloro-2'-fluorobenzophenone,38.0 g (0.3 moles) of 2,2-dichloro propanal; 18.0 g (0.11 moles) ofhydroxylamine sulfate and 500 ml of 2B ethanol was stirred at roomtemperature for 2 days.

The mixture was diluted with 200 ml of 10% aqueous Na₂ CO₃ solution withvigorous agitation. A gummy material precipitated from solution and thesolution was diluted with 1.0 l of ice-water. The solution was extractedwith 3×300 ml. of dichloromethane. The extracts were combined, driedover Na₂ SO₄ ; filtered and concentrated to dryness in vacuo. Theresidue was crystallized from dichloro methane and petroleum ethergiving 6-chloro-2-(1,1-dichloroethyl)-1,2-dihydro-4-(2-fluorophenyl)quinazoline 3-oxide as yellow prisms, m.p. 195°-198° dec.

EXAMPLE 347-Chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiazepine4-oxide

3.8 ml of Nitromethane was added to 50.0 ml of dimethylformamide withstirring and under an atmosphere of nitrogen. The solution was chilledto 0° and 1.3 g (0.012 mols) of potassium tertiary butoxide was added inportions. The temperature was maintained at 0° to 10° by means of anice-H₂ O bath. The mixture was stirred at room temperature for 1 hour.

The mixture was chilled to 5° with stirring and 2.2 g (0.006 moles) ofthe quinazoline of Example 33 was added at 5° to 9° in portions. Afterthe addition had been completed, the mixture was stirred at roomtemperature for 17 hours.

The reaction mixture was poured into ice-H₂ O and dichloromethaneneutralizing with glacial acetic acid. The dichloromethane was washedwith water; brine and dried over Na₂ SO₄. After filtration andconcentration an amber residue was obtained which was crystallized withEtOAc. The crystals were collected and dried giving orange7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiazepine4-oxide as prisms, m.p. 198°-200°. Recrystallization from CH₂ Cl₂ -EtOAcgave pure material m.p. 216°-218° dec.

EXAMPLE 357-Chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine4-oxide

9.5 ml of Nitromethane was dissolved in 100 ml of dimethylformamideunder nitrogen and with stirring. 5.0 g (0.045 moles) of potassiumtertiary butoxide was added at 0°-10° and the mixture was stirred atroom temperature for 1 hour. The mixture was then chilled on ice and 5.1g (0.015 moles) of6-chloro-2-dichloromethyl-1,2-dihydro-4-phenylquinazoline 3-oxide wasadded slowly at a temperature <9°. The reaction mixture was stirred atroom temperature for 17 hours.

The mixture was poured onto ice-H₂ O and dichloromethane and madeslightly acid with glacial acetic acid. The aqueous phase wasre-extracted three times with dichloromethane. The organics werecombined; washed consecutively with water and brine, dried over Na₂ SO₄; filtered and concentrated to dryness in vacuo giving an amber residue.Crystallization from boiling ethanol afforded yellow prisms, mp245°-248° dec. Admixture with authentic material gave no depression inmelting point.

EXAMPLE 367-Chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiazepine4-oxide

Potassium tert. butoxide, 3.37 g (0.03 m), was added to a stirredsuspension of 3.5 g (0.01 m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine4-oxide in 100 ml of dimethylformamide cooled at -20°. After stirringunder nitrogen for 10 min at this temperature 2.13 g (0.015 m) ofmethyliodide was added and stirring was continued for 10 min. Thereaction mixture was neutralized by addition of glacial acetic acid andwas partitioned between water and methylene chloride. The organic phasewas separated, dried over sodium sulfate and evaporated. The residue wascrystallized from methylene chloride/ethyl acetate to yield yellowcrystals with mp 215°-218°. The analytical sample was recrystallizedfrom the same solvents, mp 216°-218°.

EXAMPLE 372-Aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinedimaleate

A mixture of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-carboxamide(64 mg., 0.2 mmole) and lithium aluminum hydride (15 mg., 0.4 mmole) indry THF (3 ml) was boiled for 15 min. The cooled reaction mixture wasquenched by addition of saturated aqueous sodium sulfate solution. Theanalysis of the resulting solution showed the presence of startingmaterial as the major, more mobile component and the free base2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepineas the minor component. The solution was transferred directly to a 20×20cm² preparative tlc plate (silica gel) and the plate was developed withethanol. The lower yellow band was removed and extracted twice withmethanol/methylene chloride (2:1). Evaporation of the filtered extractleft a clear, colorless oil. This was taken up in ethanol (1 ml),treated with excess maleic acid (50 mg), scratched and stored overnightin the freezer. The yellow crystals were collected, washed with etherand air-dried. The product was identified as2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinedimaleate by comparison of its infrared spectrum in Nujol, and of itsmelting point 185°-186.5° with those of an authentic sample (mp 188°).The mixture melting point was 184°-187°.

EXAMPLE 382-Aminomethyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinedimaleate hemihydrate

A solution of 2.9 g. (0.00927 M) of2,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-1H-1,4-benzodiazepine4-oxide in a mixture of 1 teaspoon of Raney nickel, 90 ml. oftetrahydrofuran and 45 ml. of methanol was hydrogenated at atmosphericpressure and at room temperature for 2.3 hr. The mixture was filtered,and the nickel was washed with dichloromethane. The combined filtrateswere evaporated and the resulting oil was dissolved in 50 ml. ofdichloromethane which was washed with 50 ml. of dilute ammoniumhydroxide, dried over anhydrous sodium sulfate and evaporated todryness. A solution of 2.2 g. (0.019 M) of maleic acid in 15 ml. ofethanol was added to the oil and after ether was added the productcrystallized. Recrystallization from a mixture of methanol and ethergave a product as yellow rods, m.p. 147°-150°.

EXAMPLE 393a,4-Dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5a][1,4]benzodiazepine

A solution of 4.0 g. (0.0149 M) of the base of2-aminomethyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinedimaleate hemihydrate in 125 ml. of absolute ethanol was treated with 4g. (0.0247 M) of triethylorthoacetate and 0.5 g. (0.00263 M) ofp-toluene sulfonic acid. After refluxing the mixture for 2 hr. thereaction was evaporated to dryness. The resulting oil was dissolved in50 ml. of dichloromethane, which was washed with 50 ml. of diluteammonium hydroxide, dried over anhydrous sodium sulfate and evaporatedto dryness to yield the crude product as an oil.

EXAMPLE 406-(2-Fluorophenyl)-1-methyl-4H-imidazo-[1,5a][1,4]benzodiazepine

The crude product from the previous example was dissolved in 100 ml. oftoulene, treated with 18 g. of activated manganese dioxide and themixture was stirred and refluxed for 3.5 hr. using a Dean Stark trap.The reaction mixture as filtered through Celite and the precipitate waswashed with 100 ml. of tetrahydrofuran and then 100 ml. ofdichloromethane. The combined filtrates were evaporated and the residuewas dissolved in 25 ml. of dichloromethane. This solution waschromatographed through a Florisil column with dichloromethane, and theneluted with ether. Elution with ethyl acetate and then a 10% (v/v)solution of methanol in ethyl acetate gave the crude product, which wascrystallized from ether and then recrystallized from ethyl acetate togive the product as white prisms, m.p. 164°-168°.

EXAMPLE 41

A solution of 1.2 g. (0.0041 M) of3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepinein 50 ml. of mesitylene and 0.5 g. of 10% palladium on charcoal wasstirred and refluxed for 28 hr., and then it was filtered and evaporatedto dryness. Crystallization from ethyl acetate gave the product ofExample 40 as white prisms, m.p. 162°-167°, and a mixed m.p. withauthentic product melted at 162°-168°.

EXAMPLE 426-(2-Fluoro-5-nitrophenyl)-1-methyl-4H-imidazo[1,5a][1,4]benzediazepine

A solution of 0.3 g. (0.00103 M) of6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 2ml. of concentrated sulfuric acid was cooled to 0°, and a solution of0.11 g. (0.0011 M) of potassium nitrate in 1.5 ml. of concentratedsulfuric acid was added dropwise. After 18 hr. at room temperature anadditional 20 mg. (0.0002 M) of potassium nitrate was added and thereaction was stirred for 5 hr. and then poured into a beaker containingice. The mixture was made basic with ammonium hydroxide, and extractedwith 50 ml. of dichloromethane which was separated, dried over anhydroussodium sulfate, and evaporated to dryness. The oil was dissolved in 3ml. of dichloromethane and applied to a silica gel thick layer platewhich was developed in a mixture of ethyl acetate and ethanol (3:1). Theproduct was scraped off the plate and stirred with a 1:1 (v/v) mixtureof methanol and dichloromethane and filtered. The filtrates wereevaporated and the residue was crytallized from methanol.Recrystallization of the product from a mixture of dichloromethane andpetroleum ether gave the nitrated product a white prisms, m.p.199°-203°.

EXAMPLE 432-Chloromethyl-4-(2-fluorophenyl)-6-nitro-1,2-dihydroquinazoline 3-oxide

A mixture of 100 g. (0.8 m) of chloroacetaldehyde dimethylacetal and 100ml. of 1.5 N hydrochloric acid was heated under reflux for 15 min. andthen cooled and added to a solution of 130 g. (0.5 m) of2-amino-2'-fluoro-5-nitrobenzophenone and 46 g. (0.28 m) ofhydroxylamine sulfate and 1 l. of ethanol. The mixturewas stirred atroom temperature for 2 hr. and then heated to reflux for 1.5 hr. Themixture was cooled and the product obtained by filtration.Recrystallization from a mixture of chloroform and methanol gave thepure product as yellow prisms, m.p. 220°-224°.

EXAMPLE 44 2-Chloromethyl-4-(2-fluorophenyl)-6-nitroquinazoline 3-oxide

A solution of 142 g. (0.423 m) of2-chloromethyl-4-(2-fluorophenyl)-6-nitro-1,2-dihydroquinazoline 3-oxidein 2.3 l. of dichloromethane was treated with 400 g. of manganesedioxide, and after stirring for 18 hr. the solution was filtered. Themanganese dioxide was washed with 600 ml. of tetrahydrofuran and 600 ml.of dichloromethane. The combined filtrates were concentrated to 400 ml.and 1 l. of ether was added. This was cooled and filtered to give afinal product. A sample ws recrystallized from a mixture ofdichloromethane and methanol to give the pure product as pale yellowprisms, m.p. 127°-130°.

EXAMPLE 451,3-Dihydro-5-(2-fluorophenyl)-7-nitro-2-nitromethylene-2H-1,4-benzodiazepine4-oxide

To 500 ml. of dimethylsulfoxide and 75 ml. (1.4 m) of nitromethane wasadded with stirring under nitrogen 15.6 g. (0.678m) of lithium amide.After 30 minutes the solution was cooled to 5° C. and 104 g. (0.31 m) of2-chloromethyl-4-(2-fluorophenyl)-6-nitroquinazoline 3-oxide was addedslowly, keeping the temperature below 8° C. After 68 hr. at roomtemperature the reaction was poured into a mixture of 2.5 l. of ice andwater and 25 ml. of acetic acid, and the solution was filtered. Thegummy precipitate was dissolved in 1 l. of dichloromethane which waswashed with dilute ammonium hydroxide, dried over anhydrous sodiumsulfate and evaporated. The residue was crystallized from ethyl acetateto give a final product, and the filtrates were evaporated, dissolved indichloromethane and filtered through a sintered glass funnel containing200 g. of Florisil. The Florisil was eluted with dichloromethane (600ml.), ether (600 ml.) and ethyl acetate (1.2 l.). The ether and ethylacetate fractions were combined and concentrated to give additionalfinal product. A sample was recrystallized from a mixture oftetrahydrofuran and hexane to give the pure product as yellow prisms,m.p. 216°-220°.

EXAMPLE 468-Amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5-a][1,4]benzodiazepineisopropanolate

A suspension of 25 g. (0.0698 m) of1,3-dihydro-5-(2-fluorophenyl)-7-nitro-2-nitromethylene-2H-1,4-benzodiazepine4-oxide in 1.3 l. of absolute ethanol was treated with 10 teaspoons ofRaney nickel and hydrogenated at atmospheric pressure and roomtemperature for 9 hr. The mixture was filtered through Celite and thefiltrate was evaporated to dryness. A sample of the oil was crystallizedfrom tetrahydrofuran to give the intermediate7-amino-2-aminomethyl-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepineas yellow prisms which melted with decomposition at 185°-192°.

Without further purification, the oil obtained from the reduction washeated under reflux for 2 hr. in a solution of 300 ml. of absoluteethanol, containing 4.5 ml. (0.0257 m) of ethanolic hydrogen chlorideand 50 g. (0.309 m) of triethylorthoacetate. The mixture was thenevaporated to dryness and the residue was dissolved in 150 ml. ofdichloromethane which was wshed with 100 ml. of dilute ammoniumhydroxide, dried over anhydrous sodium sulfate and evaporated todryness.

The residual oil, which was crude8-acetylamino-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazeine,was dissolved in 500 ml. of benzene and treated with 100 g. of activatedmanganese diode. The mixture was refluxed and stirred for 9 hr. using aDean Stark trap. An additional 25 g. of activated manganese dioxide wasadded and after 4 hr. of refluxing the manganese dioxide was removed byfiltration and was washed with 500 ml. of tetrahydrofuran. The filtrateswere combined and evaporated to dryness. The residual oil, which was8-acetylamino-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5-a][1,4]benzodiazepine,was dissolved in 75 ml. of methanol and an excess of ethanolic hydrogenchloride was added. After 10 min. 100 ml. of water was added, and afteran additional 20 min, during which time the 8-acetyl group washydrolyzed, a mixture of ice and dilute ammonium hydroxide was addeduntil the solution was basic. The reaction was filtered and theprecipitate and filtrates were extracted separately withdichloromethane. The extracts were dried, and evaporated. The extractfrom the filtrates were crystallized from isopropanol to give a finalproduct, and the extract from the precipitate was chromatographedthrough Florisil, first with dichloromethane and then with ether andethyl acetate containing 10% (v/v) of methanol gave, after evaporationand crystallization from isopropranol, additional product.Recrystallization of the combined products from isopropanol gave theisopropanolate as white rods, m.p. 135°-145°.

EXAMLE 47(+)-8-Chloro-1,4-dimethyl-6-(7-fluorophenyl)-4H-imidazo[1,5-a][1,4]-benzodiazepine1-tartrate

A mixture of 17 g. (0.05 m) of racemic8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine which had been liberated from its dihydrochloride bypartitionining between methylene chloride and aqueous ammonia, 18.8 g.(0.05 m) of O,O'-dibenzoyl-d-tartaric acid hydrate and 170 ml. ofethanol was boiled until solution was complete. For crystallization thesolution was allowed to sit overnight. The separated crystals werecollected, washed with ethanol and ether to yield product with m.p.140°-142°. Recrystallization from ethanol/ether yielded product withm.p. 141°-142° and [α]_(D) ²⁵ -43.39 (c=1% in methanol).

A solution of 1.6 g. (0.0106 m) of 1-tartaric acid in 11 ml. of ethanolwas added to a solution of 3.5 g. of the levorotatory base liberatedfrom the above O,O'-dibenzoyl-d-tartrate in 11 ml. of ethanol. Thecrystals obtained were collected and washed with ethanol and ether toyield product with m.p. 178°-180°. Recrystallization from ethanol gaveproduct with m.p. 183°-185° and [α]_(D) ²⁵ +25.69° (c=1.012% inmethanol). The amorpous base liberated from this salt showed a rotationof [α]_(D) ²⁵ -36.74° (c=0.939% in methylene chloride).

EXAMPLE 48(-)-8-Chloro-1,4-dimethyl-6-(1-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepined-tartrate

The mother liquor left after separation of the crystalline salt withO,O'-dibenzoyl-d-tartaric acid described in the preceding example wasevaporated and recovered to the base by partitioning between aqueousammonia and methylene chloride. The methylene chloride solution wasdried over sodium sulfate and evaporated to yield 12 g. of partlyresolved base.

A solution of 9.7 g. (0.029 m) of this material in 15 ml. of ethanol wastreated with a solution of 4.4 g. of d-tartaric acid in 14 ml. ofethanol. The crystals which separated after several hours were collectedto yield product with m.p. 176°-178°. Recrystallization from ethanolgave product with m.p. 182°-184° and [α]_(D) ²⁵° -24.96° (0.9616% inmethanol). The amorphous base liberated from this salt showed a rotationof [α]_(D) ²⁵° +37.6° (c=1.0% in methylene chloride).

EXAMPLE 498-Chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine

Potassium t-butoxide, 0.625 g. (5.5 mmol), was added to a solution of1.625 g. (5 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 20 ml. of dimethylformamide cooled to -30°. After stirring undernitrogen for 10 min. at -30° the dark mixture was acidified with 1 ml.of glacial acetic acid and was then partitioned between aqueousbicarbonate and toluene/methylene chloride (3:1 v/v). The organic layerwas separated, dried and evaporated. The residue was chromatographedover 60 g. of silica gel using 25% (v/v) methylene chloride in ethylacetate. The less polar product was eluted first and was crystallizedfrom ethylacetate/hexane to yield product with m.p. 180°-181°.

EXAMPLE 508-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Potassium t-butoxide, 0.125 g. (1.1 mmol) ws added to a solution of0.325 g. (1 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepinein 20 ml. of dimethylformamide cooled to -30°. After stirring at -30° to-20° for 15 min., the reaction mixture was acidified by addition of 0.2ml. of glacial acetic acid and was partitioned between aqueous sodiumbicarbonate and methylene chloride toluene (1:3). The organic phase waswashed with water, dried and evaporated. The residue was chromatographedover 20 g. of silica gel using ethyl acetate for elution. After elutionof starting material, product was collected and crystallized fromether/hexane, m.p. 156°-158°.

EXAMPLE 517-(2-Methyl-1,3-dioxolan-2-yl-2[bis(morpholino)phosphinyloxy]5-phenyl-3H-1,4-benzodiazepine

A solution of 19.3 g. (0.06 m) of1,3-dihydro-7-(2-methyl-1,3-dioxolan-2-yl)-5-phenyl-2H-1,4-benzodiazepin-2-onein 300 ml. of dry tetrahydrofuran was treated under an atmosphere ofargon with 3.1 g. (0.075 m) of a 57% suspension of sodium hydride inmineral oil. The mixture was heated under reflux for 1 hr., cooled toroom temperature when 22.2 g. (0.087 m) of dimorpholinophosphinischloride was added. The mixture was allowed to stir at room temperaturefor 2 hr. and then stand overnight. Sodium chloride was removed byfiltration and the crude product was obtained by removal of the solventand crystallization of the residue from ether.

EXAMPLE 522,3-Dihydro-7-(2-methyl-1,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-1H-1,4-benzodiazepine

A mixture of 100 ml. of dry N,N-dimethylformamide and 6.8 g. ofnitromethane was treated under an atmosphere of argon with 2.8 g. (0.066m) of a 57% suspension of sodium hydride in mineral oil. The mixture wasstirred for 1 hr. at room temperature when a solution of 18 g. (0.033 m)of crude 7-(2-methyl-1,3-dioxolan-2-yl)-2[bis(morpholino)phosphinyloxy]5-phenyl-3H-1,4-benzodiazepine in 50 ml. of dry N,N-dimethylformamidewas added. The reaction mixture was allowed to stand at room temperaturefor 15 hrs. when the dark viscous liquid was poured over a mixture ofice and dilute acetic acid. The bright yellow precipitate was removed byfiltration, dissolved in dichloromethane which was washed with diluteammonium hydroxyide and water, dried over anhydrous sodium sulfate andevaporated. The original filtrate was extracted with dichoromethanewhich was washed, dried and evaporated as above. The two crude residueswere combined and chromatographed over Florisil. Using dichloromethane,10% (v/v) ether as the eluent and monitoring the fractions by tlc,several fractions containing the product were collected and evaporated.Crystallization and recrystallization from a mixture of dichloromethaneand hexane gave the pure product as pale yellow prisms, m.p. 158°-161°.

EXAMPLE 531,3-Dihydro-7-ethyl-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine

Sodium nitrite 8.6 g., (0.125 m) was added in three portions over a 1/2hour period to a solution of 29.5 g. (0.1 m) of7-ethyl-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine in 100ml. of glacial acetic acid. After stirring for another 1/2 hour at roomtemperaure, the mixture was diluted with ice-water and extracted withmethylene chloride. The extracts were washed with water and aqueousbicarbonate, dried over sodium sulfate and evaporated to leave 21.7 g.of crude7-ethyl-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepineas a yellow oil.

This material was dissolved in 100 ml. of dimethylformamide and thesolution was added to a mixture of 100 m. of dimethylformamide, 35 ml.of nitromethane and 9.9 g. of potassium t-butoxide which had beenstirred for 1/2 hour at room temperature. After completed addition, thereaction mixture was stirred for 1 hour at room temperature and for 30minutes on the steam bath. The cooled solution was acidified withglacial acetic acid, diluted with water and extracted with methylenechloride. The extracts were washed with water, dried and evaporated. Theresidue was dissolved in 50 ml. of ethanol and was allowed tocrystallize in the partitioning between methylene chloride and aqueousammonia. The methylene chloride layer was dried and evaporated.Crystallization of the residue from ether/hexane yielded a product withm.p. 152°-154°. Refrigerate overnight after seeding. The yellow crystalswere collected and recrystallized from ethanol, m.p. 138°-140°. Seedcrystals were obtained by chromatography of the crude product over40-fold amount of silica get using 5% (v/v) of ethylacetate in methylenechloride. The analytical sample was recrystallized from ether/hexane,m.p. 138°-141°.

EXAMPLE 54 8-Ethyl-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1,4]benzodiazepine

1,3-Dihydro-7-ethyl-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine,2.6 g., was hydrogenated for 4 hours with Raney nickel (1 teaspoonful)in 30 ml. of ethanol. The catalyst was separated by filtration and thefiltrate was evaporated. The residue was dissolved in ether and theamine was extracted with 10% aqueous acetic acid. The extracts werewashed with ether and made alkaline with ammonia. The precipitated aminewas extracted with methylene chloride. The extracts were dried andevaporated to leave 1.5 g. of crude2-aminomethyl-2,3-dihydro-7-ethyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine.This material was dissolved in 50 ml. of xylene. The solution was thenheated to reflux for 2 hours after addition of 3 ml. oftriethylorthoacetate. The residue obtained after evaporation underreduced pressure was chromatographed over 50 g. of silica get using 20%methanol in methylene chloride. The homogeneous fractions were combinedand evaporated to yield3a,4-dihydro-8-ethyl-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine. This material was dissolved in 50ml. of toluene and the solution was heated to reflux for 1 hour afteraddition of 5 g. of activated manganese dioxide. The inorganic materialwas separated by filtration and the filtrate was evaporated. The residuewas dissolved in ether and treated with ethanolic hydrogen chloride andacetone. The crystalline dihydrochloride (m.p. 248°-255°) was collectedand reconverted to the base by

EXAMPLE 55 Parenteral Formulation

    ______________________________________                                        Each 1 cc ampul contains    Per cc                                            ______________________________________                                        8-Chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo                               [1,5-a][1,4]benzodiazepine maleate                                                                        1.0 mg.                                           Benzyl Alcohol              0.15 cc                                           Tartaric Acid Adjusted with Sodium hydroxide                                  100% solution               3.0-4.0                                           Water for Injection, U.S.P. 1 cc. ad                                          ______________________________________                                    

Procedure (For 10,000 cc):

1. In a clean glass or glass-lined vessel, 8,000 cc of Water forInjection were heated to 90° C. It was then cooled to 50°-60° C., andbenzyl alcohol was added and dissolved with stirring. The solution wasthen allowed to cool to room temperature.

2. The 10.0 grams of 8-chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a] [1,4]benzodiazepine maleate were added under and atmosphere ofnitrogen and stirred unitl completely dissolved.

3. The pH was now adjusted to 3.0±1.0, preferably 3.0±0.5 with acombination of tartaric acid buffer and sodium hydroxide solution.

4. Sufficient Water for Injection was then added to make a total volumeof 10,000 cc.

5. This solution was then filtered through an 02 Selas Candle, filledinto suitable size ampuls, gassed with nitrogen and sealed.

EXAMPLE 56 Tablet Formulation

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        8-Chloro-1-methyl-6(2-fluorophenyl)-                                          4H-imidazo[1,5-a][1,4]-                                                       benzodiazepine maleate   10.0 mg.                                             Lactose                  113.5 mg.                                            Corn Starch              70.5 mg.                                             Pregelatinized Corn Starch                                                                             8.0 mg.                                              Calcium Stearate         3.0 mg.                                              Total Weight             205.0 mg.                                            ______________________________________                                    

Procedure:

1.8-Chloro-1-methyl-6(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate was mixed with the lactose, corn starch and pregalatinized cornstarch in a suitable size mixer.

2. The mix was passed through a Fitzpatrick Comminuting machine fittedwith #1A screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thickpaste. The moist mass was passed through a #12 screen and the moistgranules were dried on paper lined trays at 110° F.

4. The dried granules were returned to the mixer, calcium stearate wasadded and mixed well.

5. The granules were compressed at a tablet weight of 200 mg. usingstandard concave punches having a diameter of 5/16".

EXAMPLE 57 Tablet Formulation

    ______________________________________                                                                Per Tablet                                            ______________________________________                                        8-Chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo                               [1,5-a][1,4]benzodiazepine maleate                                                                      25.00 mg.                                           Lactose, U.S.P.           64.50 mg.                                           Corn Starch               10.00 mg.                                           Magnesium Stearate         0.50 mg.                                           ______________________________________                                    

Procedure:

1.8-Chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleatewas mixed with the lactose, corn starch and magnesium stearate in asuitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine fitted with a #1A screen with knives forward.

3. The mixed powders were slugged on a tablet compressing machine.

4. The slugs were comminuted to a suitable mesh size (#16 screen) andmixed well.

5. The tablets were compressed at a tablet weight of 100 mg. usingtablet punches having a diameter of approximately 1/4". (Tablets may beeither flat or biconvex and may be scored if desired.)

EXAMPLE 58 Capsule Formulation

    ______________________________________                                                                Per Capsule                                           ______________________________________                                        8-Chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo                               [1,5-a][1,4]benzodiazepine maleate                                                                      25 mg.                                              Lactose                   158 mg.                                             Corn Starch               37 mg.                                              Talc                       5 mg.                                              Total Weight              225 mg.                                             ______________________________________                                    

Procedure:

1.8-Chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleatewas mixed with the lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a #1A screen with knives forward.

3. The blended powder was returned to the mixer, the talc added andblended thoroughly. The mixture was then filled into #4 hard shellgelatin capsules on a Parke Davis capsulating machine. (Any similar typemachine may be used.)

EXAMPLE 59 Capsule Formulation

    ______________________________________                                                                Per Capsule                                           ______________________________________                                        8-Chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo                               [1,5-a][1,4]benzodiazepine maleate                                                                      50 mg.                                              Lactose, U.S.P.           125 mg.                                             Corn Starch, U.S.P.       30 mg.                                              Talc, U.S.P.               5 mg.                                              Total Weight              210 mg.                                             ______________________________________                                    

Procedure:

1.8-Chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleatewas mixed with lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a #1A screen with knives forward.

3. The blended powder was returned to the mixer, the talc added andblended thoroughly.

4. The mixture was filled into #4 hard shell gelatin capsules on a ParkDavis capsulating machine.

EXAMPLE 60 Capsule Formulation

    ______________________________________                                                              Per Capsule                                             ______________________________________                                        8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-                                  imidazo[1,5-a][1,4]benzodiazepine maleate                                                             50 mg.                                                Lactose, U.S.P.         125 mg.                                               Corn Starch, U.S.P.     30 mg.                                                Talc, U.S.P.             5 mg.                                                Total Weight            210 mg.                                               ______________________________________                                    

Procedure:

1.8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate was mixed with lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a #1A screen with knives forward.

3. The blended powder was returned to the mixer, the talc added andblended thoroughly.

4. The mixture was filled into #4 hard shell gelatin capsules on a ParkeDavis capsulating machine.

EXAMPLE 61 Capsule formation

    ______________________________________                                                              Per Capsule                                             ______________________________________                                        8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-                                  imidazo[1,5-a][1,4]benzodiazepine maleate                                                             25 mg.                                                Lactose                 258 mg.                                               Corn Starch             37 mg.                                                Talc                     5 mg.                                                Total Weight            225 mg.                                               ______________________________________                                    

Procedure:

1. 8Chlor-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine maleate was mixed with the lactose and corn starch in asuitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a #1A screen with knives forward.

3. The blended powder was returned to the mixer, the talc added andblended thoroughly. The mixture was then filled into #4 hard shellgelatin capsules on a Park Davis capsulating machine. (Any similar typemachine may be used.)

EXAMPLE 62 Tablet Formulation

    ______________________________________                                                                 Per Tablet                                           ______________________________________                                        8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo                           [1,5-a][1,4]benzodiazepine maleate                                                                       25.00 mg.                                          Lactose, U.S.P.            64.50 mg.                                          Corn Starch                10.00 mg.                                          Magnesium Stearate          0.50 mg.                                          ______________________________________                                    

Procedure:

1.8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate was mixed with the lactose, corn starch and magnesium stearatein a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine fitted with a #1A screen with knives forward.

3. The mixed powders were slugged on a tablet compressing machine.

4. The slugs were comminuted to a suitable mesh size (#26 screen) andmixed well.

5. The tablets were compressed at a tablet weight of 100 mg. usingtablet punches having a diameter of approximately 1/4". (Tablets may beeither flat or biconvex and may be scored if desired.)

EXAMPLE 63 Tablet Formulation

    ______________________________________                                                                 Per Tablet                                           ______________________________________                                        8-Chloro-1,4-dimethyl-6(2-fluorophenyl)-4H-imidazo                            [1,5-a][1,4]benzodiazepine maleate                                                                       10.0 mg.                                           Lactose                    113.5 mg.                                          Corn Starch                70.5 mg.                                           Pregelatinized Corn Starch  8.0 mg.                                           Calcium Stearate            3.0 mg.                                           Total Weight               205.0 mg.                                          ______________________________________                                    

Procedure:

1.8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemealeate was mixed with the lactose, corn starch and pregelatinized cornstarch in a suitable size mixer.

2. The mix was passed through a Fitzpatrick Comminuting machine fittedwith #1A screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thickpaste. The moist mass was passed through a #12 screen and moist granuleswere dried on paper lined trays at 110° F.

4. The dried granules were returned to the mixer, the calcium stearatewas added and mixed well.

5. The granules were compressed at a tablet weight of 200 mg. usingstandard concave punches having a diameter of 5/16".

EXAMPLE 64 Parenteral Formulation

    ______________________________________                                        Each 1 cc ampul contains:  Per cc                                             ______________________________________                                        8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-                                  imidazo[1,5-a][1,4]benzodiazepine maleate                                                                1.0 mg.                                            Benzyl Alcohol             0.15 cc.                                           Tartaric Acid adjusted with Sodium Hydroxide                                  100% solution              3.0-4.0                                            Water for Injection, U.S.P.  q.s. ad                                                                     1 cc.                                              ______________________________________                                    

Procedure (For 10,000 cc):

1. In a clean glass or glass-lined vessel, 8,000 cc of Water forInjection were heated to 90° C. It was then cooled to 50°-60° C., andbenzyl alcohol was added and dissolved with stirring. The solution wasthen allowed to cool to room temperature.

2. The 10.0 grams of8-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate were added under an atmosphere of nitrogen and stirred untilcompletely dissolved.

3. The pH was now adjusted to 3.0±1.0, preferably 3.0±0.5 with acombination of tartaric acid buffer and sodium hydroxide solution.

4. Sufficient WATER FOR Injection was then added to make a total volumeof 10,000 cc.

5. This solution was then filtered through an 02 Sedas candle, filledinto suitable size ampuls, gassed with nitrogen and sealed.

EXAMPLE 651-Acetyl-2-acetylaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine

2-Aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinedimaleate, 8.0 g (0.015 m) was partitioned between methylene chlorideand aqueous ammonia. The methylene chloride solution was washed withwater, dried over sodium sulfate and evaporated. The residue wasdissolved in 50 ml of pyridine. After addition of 10 ml of aceticanhydride the mixture was heated on the steam bath for 4 hours. Thereagents were evaporated under reduced pressure and the residue waspartitioned between methylene chloride and aqueous sodium bicarbonatesolution. The organic layer was dried and evaporated. Crystallization ofthe residue from methylene chloride/ether with seeding yielded a finalproduct with mp. 213°-215°. Seeds were obtaned by chromatography oversilica gel (40 fold amount) using 10% (v/v) ethanol in methylenechloride for elution. The analytical sample was recrystallized fromethylacetate/hexane and had mp. 215°-217°.

EXAMPLE 668-Chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 0.5 g of1-acetyl-2-acetylaminomethyl-7-chlor-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepineand 10 g of polyphosphoric acid was heated to 150°-170° for 10 min. Thecool reaction mixture was dissolved in ice-water and the solution wasmade alkaline with ammonia. The precipitated base was extracted withmethylene chloride. The extracts were washed with water, dried oversodium sulfate and evaporated. The residue was chromatographed over 10 gof silica gel using 20% methanol in methylene chloride. The cleanfractions were combined and evaporated. The residue was crystallizedfrom ether to yield a final product with mp. 142°-144°.

EXAMPLE 678-Chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a]benzodiazepinemaleate

41.3 g. of8-chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinedihydrochloride was partitioned between methylene chloride and aqueousammonia. The methylene chloride solution was washed with water, driedover sodium sulfate and evaporated to leave 34 g. of free base. Thismaterial was dissolved in 50 ml of 2-propanol and the solution wastreated with a solution of 12 g. of maleic acid in 40 ml of 2-propanol.The solution was gradually diluted with 300 ml of ether. Theprecipitated crystals were collected and dried to leave the maleate saltwith m.p. 130°-132° after recrystallization from ethanol/ether.

EXAMPLE 687-Chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-phenyl-2H-1,4-benzodiazepine*

A mixture of 40.8 g. (0.1 m) of7-chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-phenyl-2H-1,4-benzodiazepine4-oxide, 250 ml. of methanol, 250 ml. of tetrahydrofuran and 1tablespoonful of Raney nickel was hydrogenated at atmospheric pressurefor 5 hours. The catalyst was removed by filtration and the filtrate wasevaporated. Crystallization of the residue from methylenechloride/2-propanol yielded colorless crystals with m.p. 160°-163°. Foranalysis it was recrystallized from 2-propanol, m.p. 165°-166°.

A second modification of crystals with m.p. 138°-140° was obtained insome instances.

EXAMPLE 697-Chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-phenyl-2H-1,4-benzodiazepine*

Phosphorus trichloride, 4 ml., was Added to a solution of 4 g. (0.01 m)of7-chloro-1,3-dihydro-2-(2-dimethoxymalonylidene)-5-phenyl-2H-1,4-benzodiazepine4-oxide in 100 ml. of methylene chloride. After sitting at roomtemperature overnight, the solution was washed with 10% aqueous sodiumcarbonate solution. The methylene chloride layer was dried andevaporated. Crystallization of the residue from 2-propanol andrecrystallization from methylene chloride/2-propanol yielded productwith m.p. 165°-166°.

EXAMPLE 707-Chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-(2-fluorophenyl-2H-1,4-benzodiazepine

Sodium nitrite 27.6 g. (0.4 m) was added in portions over a period of 30minutes to a solution of 90.45 g. (0.3 m) of7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine in 400ml. of glacial acetic acid. Following completed addition, the mixturewas stirred at room temperature for 1 hour and was diluted with 1 l. ofwater and extracted with methylene chloride. The extracts were washedtwice with water and then with 10% aqueous sodium carbonate solution.The solution was drid and evaporated to yield crude7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepineas a yellow oil.

This material was dissolved in 300 ml. of dimethylformamide and wasadded to a mixture of 150 ml. of dimethyl malonate, 40.4 g. of potassiumt-butoxide and 500 ml. of dimethylformamide which had been stirred atroom temperature for 10 minutes. The reaction mixture was stirred undernitrogen overnight at room temperature, was acidified by addition of 50ml. of glacial acetic acid, diluted with water and extracted withmethylene chloride. The extracts were washed with water and aqueoussodium carbonate solution, were dried over sodium sulfate andevaporated. Crystallization of the residue from ethanol yieldedcolorless crystals with m.p. 170°-172°. For analysis the product wasrecrystallized from methylene chloride/ethanol, m.p. unchanged.

EXAMPLE 717-Chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-phenyl-2H-1,4-benzodiazepine4-oxide*

Potassium t-butoxide, 26 g. (0.232 m) was added to a mixture of 300 ml.of dimethylformamide and 50 ml. (0.44 m) of dimethyl malonate. Afterstirring under nitrogen for 10 minutes a solution of 66 g. )0.209 m) of7-chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxidein 100 ml. of dimethyl formamide was added over a 10 minute period. Themixture was then slowly heated on the steam bath and kept for 10 minutesat 65°. After cooling to room temperature 40 ml. of glacial acetic acidwas added followed by 1 l. of water over a period of 30 minutes withoccasional scratching. The precipitated crystals were collected, washedwith water and dissolved in methylene chloride. The solution was driedover sodium sulfate and concentrated to a small volume. The product wascrystallized by addition of hexane to yield product with m.p. 188°-190°.The analytical sample was recrystallized from methylene chloride/hexane,m.p. 194°- 195°.

EXAMPLE 727-Chloro-1,3-dihydro-2-(methoxycarbonylmethylene)-5-phenyl-2H-1,4-benzodiazepine

A mixture of 115 g. (0.3 m) of7-chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-phenyl-2H-1,4-benzodiazepine,1.5 l. of methanol and 14.4 g. (0.36 m) of sodium hydroxide was heatedto reflux for 5 hours under an atmosphere of nitrogen. The cool reactionmixture was gradually diluted with 2.5 l. of water with ice cooling. Theprecipitated crystals were collected, washed with water and dried invacuum at 60° to yield an off-white product with m.p. 167°-170°. Theanalytical sample was recrystallized from ether, m.p. 171°-173°.

EXAMPLE 737-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2-(methoxycarbonylmethylene)-2H-1,4-benzodiazepine

A mixture of 20 g. (0.05 m) of7-chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-(2-fluorophenyl)-2H-1,4:benzodiazepine,400 ml. of methanol and 3.3 g. (0.059 m) of potassium hydroxide washeated to reflux under nitrogen for 5 hours. After evaporation of thebulk of the solvent, the residue was gradually diluted with water andthe precipitated crystals were collected, washed with water and dried toleave product with m.p. 158°-160°.

For analysis it was recrystallized from methylene chloride/hexane, m.p.161-162°.

EXAMPLE 747-Chloro-1,3-dihydro-2-(methoxycarbonylmethylene)-5-phenyl-2H-1,4-benzodiazepine4-oxide

A mixture of 31 g. (0.075 m) of7-chloro-1,3-dihydro-2-(dimethoxymalonylidene)-5-phenyl-2H-1,4-benzodiazepine4-oxide, 4 g. (0.095 m) of sodium hydroxide, 300 ml. of methanol and 5ml. of water was heated to reflux for 3 hours. After cooling, themixture was diluted with water. The precipitated crystals are collectedand recrystallized from methanol to yield product with m.p. 215-216°.

EXAMPLE 757-Chloro-alpha-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-aceticacid, methyl ester

Sodium nitrite, 2.8 g. (0.04 m) was added to a solution of 8 g. (0.025m) of7-chloro-1,3-dihydro-2-(methoxycarbonylmethylene)-5-phenyl-2H-1,4-benzodiazepinein 100 ml. of glacial acetic acid. The mixture was stirred undernitrogen for 10 minutes. The product started to crystallize out after afew minutes. After dilution with 100 ml. of water, the precipitatedproduct was collected, washed with water, dried and recrystallized fromtetrahydrofuran/methanol to yield yellow crystals with m.p. 235-237°dec.

EXAMPLE 767-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid, methyl ester

Sodium nitrite, 8.8 g. (0.125 m), was added to a solution of 28 g. (0.08m) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-(methoxycarbonylmethylene)-2H-1,4-benzodiazepinein 250 ml. glacial acetic acid. The mixture was stirred at roomtemperature for 10 minutes and then diluted with 250 ml. of water. Thecrystalline product was filtered off, washed with water, methanol andether and dried to leave yellow crystals with m.p. 238°-241°. dec.

EXAMPLE 777-Chloro-alpha-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-aceticacid, methyl ester 4-oxide

Sodium nitrite, 1.4 g. (0.02 m), was added to a solution of 6.8 g. (0.02m) of7-chloro-1,3-dihydro-2-(methoxycarbonylmethylene)-5-phenyl-2H-1,4-benzodiazepine4-oxide in 100 ml. of glacial acetic acid. After stirring for 15 minutesat room temperature the reaction mixture was diluted with 100 ml. ofwater. The crystals were collected, washed with water and dried to leavea yellow product with m.p. 237°-239° dec. The analytical sample wasrecrystallized from dimethylformamide/methanol and had the same m.p.

EXAMPLE 78 Methyl8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a]benzodiazepine 3-carboxylate

7-Chloro-alpha-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-aceticacid, methyl ester, 3.6 g. (0.01 m), was dissolved in a mixture of 200ml. of tetrahydrofuran and 100 ml. of methanol by warming. Raney nickel(1 teaspoonful) was added and the mixture was hydrogenated atatmospheric pressure until hydrogen uptake flattened (1 hour and 10minutes). The catalyst was removed by filtration and the filtrate wasevaporated at the end azeotropically with toluene. The residue wasdissolved in 20 ml. of methanol. Following the addition of 3 ml. oftriethyl ortho-acetate and 0.3 ml. ethanolic hydrogen chloride (5%), thesolution was heated to reflux for 5 minutes. The residue left afterevaporation was partitioned between methylene chloride and saturatedaqueous sodium bicarbonate solution. The organic phase was separated,dried and evaporated. Crystallization of the residue from ether yieldeda product, which after recrystallization from methylenechloride/ether/hexane had m.p. 254°-256°.

EXAMPLE 79 Methyl8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

7-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid methyl ester, 11.25 g. (0.03 m) was hydrogenated as described inthe previous example with Raney nickel in a mixture of 750 ml. oftetrahydrofuran and 500 ml. of methanol. The nickel was filtered off andthe filtrate was evaporated. The residue was dissolved in 100 ml. ofmethanol and 11 ml. of triethyl orthoacetate and 5 ml. of ethanolichydrogen chloride (5%) was added. The mixture was heated to reflux for10 minutes, was evaporated and the residue was partitioned betweenmethylene chloride and aqueous sodium bicarbonate solution. Themethylene chloride solution was dried and evaporated and the residue waschromatographed over 300 g. of silica gel using methylene chloride/ethylacetate 1:3 (v/v). The clean fractions were combined and evaporated andcrystallized from ether to yield a product with m.p. 162°-164°. Theanalytical sample was recrystallized from ethyl acetate/hexane.

EXAMPLE 80 Methyl8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate

7-Chloro-5-(2-fluorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid, methyl ester, 11.25 g. (0.03 m), was dissolved in a mixture of 750ml. of tetrahydrofuran and 500 ml. of methanol by warming. Raney nickel,20 g., was added and the mixture was hydrogenated at atmosphericpressure for 4 hours. The catalyst was removed by filtration and thefiltrate was evaporated at the end azeotropically with toluene. Theresidue was dissolved in 100 ml. of methanol. After addition of 10 ml.of triethyl orthoformate and 5 ml. of ethanolic hydrogen chloride (5%),the mixture was heated to reflux for 10 minutes. It was then evaporatedand the residue was partitioned between methylene chloride and saturatedaqueous sodium bicarbonate solution. The methylene chloride layer wasseparated, dried and evaporated and the residue was crystallized fromether to yield a product which was recrystallized from methylenechloride/ether/hexane, m.p. 179°-181°.

EXAMPLE 818-Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid

A mixture of 7.3 g. (0.2 m) of methyl8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate, 2.24 g. (0.04 m) of potassium hydroxide, 200 ml. ofmethanol and 6 ml. of water was heated to reflux for 4 hours. Themethanol was partially removed under reduced pressure and the residuewas acidified with glacial acetic acid and crystallized by addition ofwater. The crystals were collected, washed with water and dried to yieldan off-white product. For analysis it was recrystallized from ethylacetate, m.p. 270°-273° dec.

EXAMPLE 828-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid

A mixture of 7.7 g. (0.02 m) of methyl8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate, 2.24 g. (0.04 m) of potassium hydroxide, 200 ml. ofmethanol and 6 ml. of water was heated to reflux for 31/2 hours. Thesolvent was partially evaporated and the residue was acidified withglacial acetic acid and diluted with water while hot. The precipitatedcrystals were collected after cooling in ice/water and were dried toyield the final product. For analysis it was recrystallized frommethylene chloride/methanol/ethyl acetate, m.p. 271°-274° dec.

EXAMPLE 38 Potassium8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate hydrate

A suspension of 1.85 g. (5 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid in 25 ml. of 2-propanol was heated on the steam bathand treated with 2.2 ml. 5N potassium hydroxide solution. After completesolution, the potassium salt was crystallized by cooling in ice/water.It was collected, washed with 2-propanol and ether and dried in highvacuum at 90° to yield colorless crystals with m.p. 245°-255°.

EXAMPLE 848-Chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid

A mixture of 1.48 g. (0.004 m) of methyl8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate, 0.5 g. (0.009 m) of potassium hydroxide, 50 ml. ofmethanol and 2 ml. of water was heated to reflux for 3 hours under anatmosphere of nitrogen. The methanol was partially evaporated and theresidue was acidified with glacial acetic acid and diluted with waterwhile the solution was still hot. The crystals were collected aftercooling in ice/water and were dried in vacuum to yield a product withm.p. 245°-247° dec.

EXAMPLE 858-Chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.73 g. (2 mmol) of methyl8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate in 50 ml. of tetrahydrofuran was added to a suspension of0.3 g. (7.5 mmol) of lithium aluminum hydride in 20 ml. oftetrahydrofuran cooled to -10°.

Following addition the mixture was stirred for 30 minutes withoutcooling and was hydrolyzed by addition of 2 ml. of water. The inorganicmaterial was filtered off and the filtrate was dried and evaporated.Crystallization of the residue from methylene chloride/ether/hexaneyielded colorless crystals with m.p. 252-255°.

EXAMPLE 868-Chloro-6-(2-fluorophenyl)-3-hydroxymethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 7.7 g. (0.02 m) of methyl8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate in 100 ml. of tetrahydrofuran was added at 0°-5° to asuspension of 2 g. (0.05 m) of lithium aluminum hydride in 100 ml. ofether. After addition the mixture was stirred for 15 minutes withoutcooling and then hydrolyzed by addition of 15 ml. of water. Theinorganic material was separated by filtration and washed with methylenechloride. The filtrate was dried and evaporated. Crystallization of theresidue from methylene chloride/ether/hexane yielded a product which wasrecrystallized from ethyl acetate/methanol for analysis, m.p. 233°-235°.

EXAMPLE 878-Chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine and8-chloro-6-(2-fluorophenyl)-6H-imidazo[1,5-a][1,4]benzodiazepine

A suspension of 1.5 g. of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid in 10 ml. of mineral oil was heated up to 230° for 5minutes. The reaction mixture was partitioned between 1N hydrochloricacid and ether. The aqueous phase was made alkaline with ammonia and wasextracted with methylene chloride. The extracts were dried andevaporated and the residue was chromatographed over 60 g. of silica gelusing 25% (v/v) methylene chloride in ethyl acetate. The less polar6H-imidazo[1,5-a][1,4]benzodiazepine was crystallized from ethyl acetateto yield colorless crystals with m.p. 195°-196°.

The more polar component was crystallized from ether to yield 4H-imidazo[1,5-a][1,4]benzodiazepine with m.p. 150°-151°.

EXAMPLE 888-Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxaldehyde

A mixture of 3 g. of8-chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine,300 ml. of methylene chloride and 15 g. of activated manganese dioxidewas stirred at room temperature for 1 hours. The manganese dioxide wasfiltered off and washed with methylene chloride. The filtrate wasevaporated and the residue was crystallized from methylenechloride/ether/hexane to yield a product with m.p. 218°-220°.

EXAMPLE 898-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxaldehyde

A mixture of 4 g. of8-chloro-6-(2-fluorophenyl)-3-hydroxymethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,200 ml. of methylene chloride and 20 g. of activated manganese dioxidewas stirred at room temperature for 1 hour. The MnO₂ was removed byfiltration and washed well with methylene chloride. The filtrate wasevaporated and the residue was crystallized from methylenechloride/ether/hexane to yield a product with m.p. 190°-192° afterrecrystallization from methylene chloride/ethyl acetate/hexane.

EXAMPLE 903-Acetoxymethyl-8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.71 g. (2 mmol) of8-chloro-6-(2-fluorophenyl)-3-hydroxymethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 20 ml. of pyridine was treated with 2 ml. of acetic anhydride. Afterstanding at room temperature overnight, the solvent was evaporated underreduced pressure and the residue was partitioned between methylenechloride and sodium bicarbonate solution. The organic phase was driedand evaporated. The residue did not crystallize and was purified bychromatography over 30 g. of silica gel using methylene chloride/ethylacetate 1:3. The homogeneous fractions were combined and evaporated. Theresidue did not crystallize and was characterized spectroscopically.

EXAMPLE 91 8-Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine 3-carboxamide

Methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate, 0.74 g. (2 mmol), was heated in 30 ml. methanolic ammoniaat 120° for 18 hours in a sealed vessel. The solvent was evaporated andthe residue was recrystallized from methylene chloride/ethanol to yieldcolorless crystals with m.p. 335°-340°.

EXAMPLE 928-Chloro-1,N-dimethyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxamide

A mixture of 0.74 g. (2 mmol) of methyl8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate and 20 ml. of ethanol containing 25% of methylamine washeated at 120° for 18 hours in a sealed vessel. The solvent wasevaporated and the residue was crystallized from methylenechloride/ethanol to yield a product with m.p. 260°-263°. The analyticalsample was recrystallized from tetrahydrofuran/ethanol.

EXAMPLE 93 Methyl8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate

Zinc dust, 2 g., was added to a solution of 1.83 g. (5 mmol) of methyl8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate in 50 ml. of methylene chloride and 10 ml. of glacialacetic acid. The mixture was stirred for 2 hours at room temperature.The inorganic material was filtered off and the filtrate was washed withdilute aqueous ammonia. The methylene chloride solution was dried andevaporated. Crystallization of the residue from methylene chloride/ethylacetate/ether yielded colorless crystals with m.p. 233°-235°. Theanalytical sample was recrystallized from ethyl acetate/methylenechloride/methanol, m.p. 234°-236°.

EXAMPLE 948-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid hydrazide

A mixture of 7.7 g. of methyl8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate, 100 ml. of isobutanol and 20 ml. of hydrazine was heatedto reflux for 1 hour. The crude product obtained after evaporation waschromatographed over 250 g. of silica gel using 5% ethanol in methylenechloride. The clean fractions were combined and evaporated.Crystallization of the residue from methylene chloride/ether yieldedcolorless crystals with m.p. 235°-237°.

EXAMPLE 958-Chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid hydrazide

A mixture of 7.4 g. of methyl8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate, 20 ml. of hydrazine and 200 ml. of isobutanol was heatedto reflux for 3 hours. After evaporation under reduced pressure, theresidue was crystallized from ethanol/ether to yield a product with m.p.225°-230°. The analytical sample was recrystallized from ethylacetate/methanol, m.p. 228°-230°.

EXAMPLE 96 Methyl8-chloro-1,4-dimethyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate

A solution of 0.73 g. (2 mmol) of methyl8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate in 20 ml. of dry dimethylformamide was cooled to -30° withstirring under nitrogen. Potassium t-butoxide, 0.25 g. (2.2 mmol) wasadded and after stirring for 5 minutes 0.3 g. (2.1 mmol) of methyliodidewas added. The mixture was allowed to reach room temperature within 1hour and was then partitioned between saturated aqueous bicarbonate andmethylene chloride. The methylene chloride layer was washed with water,dried and evaporated. Crystallization of the residue from ether yieldedcolorless crystals with m.p. 217°-221°. The analytical sample wasrecrystallized from ethyl acetate/hexane, m.p. 220°-222°.

EXAMPLE 97 Methyl8-chloro-6-(2-fluorophenyl)-4-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate

Potassium t-butoxide, 0.25 g. (2.2 mmol), was added to a solution of0.74 g. (2 mmol) of methyl8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate in 20 ml. of dimethylformamide cooled to -30°. Afterstirring for 5 minutes under nitrogen 0.32 g. (2.26 mmol) ofmethyliodide was added and the reaction mixture was allowed to warm toroom temperature within 30 minutes. It was then partitioned betweenaqueous bicarbonate and methylene chloride. The organic layer was washedwith water, dried and evaporated. The residue was crystallized fromether to yield a product, which after recrystallization from ethylacetate/hexane, had m.p. 190°-191°.

EXAMPLE 988-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldoxime

8Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde,3.4 g. (0.01 m), was partially dissolved by heating in 200 ml. ofethanol. Hydroxyamine hydrochloride, 1.05 g. (0.015 m) and 4 ml. oftriethylamine was added and the mixture was heated on the streambathuntil solution was complete. The solvent was partially evaporated andthe product was crystallized by dilution with water. The crystals werecollected, washed with ethanol and ether and dried to yield finalproduct with m.p. 280°-282° C. dec. The analytical sample wasrecrystallized from ethanol/tetrahydrofuran.

EXAMPLE 993-Aminomethyl-8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

8-Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldoxime,2.1 g., was dissolved by warming in 100 ml. of ethanol and 100 ml. oftetrahydrofuran. The solution was hydrogenated at atmospheric pressurein presence of Raney nickel (1 teaspoonful) for 3 hours. The catalystwas filtered off and the filtrate was evaporated. Crystallization of theresidue from 2-propanol/ether yielded final product. For analysis it wasrecrystallized from ethanol/ether, m.p. 217°-219° C.

EXAMPLE 1008-Chloro-3-chloromethyl-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

8-Chloro-6-(2-chlorophenyl)3-hydroxymethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,3.7 g. (0.01 m) was added with stirring to 20 ml. of thionylchloride.After stirring for 30 minutes at room temperature, the hydrochloride ofthe product was crystallized by dilution with 30 ml. of ethyl acetateand 100 ml. of ether. The crystals were collected, washed with ether andpartitioned between methylene chloride and saturated aqueous sodiumbicarbonate solution. The methylene chloride layer was dried andevaporated and the residue was crystallized from ether to yieldcolorless crystals which did not melt on slow heating but on immersionof the capillary at 200°-210° C. The analytical sample wasrecrystallized from ethyl acetate/hexane.

EXAMPLE 1018-Chloro-6-(2-chlorophenyl)-3-dimethylaminomethyl-1-methyl-4-H-imidazo[1,5-a][1,4]benzodiazepinedihydrochloride ethanolate

A mixture of 2 g. of8-chloro-3-chloromethyl-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,10 ml. of dimethylamine and 10 ml. of tetrahydrofuran was heated in asealed tube at 100° C. for 2 hours. The solvents were evaporated and theresidue was partitioned between methylene chloride and 10% aqueoussodium carbonate solution. The organic phase was dried and evaporatedand the residue was crystallized from ether to give the base with m.p.136°-138° C.

This material was dissolved in 10 ml. of ethanol and treated with twoequivalents of ethanolic hydrogen chloride. Crystallization by dilutionwith ether yielded colorless crystals which were recrystallized fromethanol/ether for analysis, m.p. 275°-277° C.

EXAMPLE 1028-Acetamido-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin

To 5 ml. of acetic anhydride was added 0.3 g. (0.00082 M) of8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepineisopropanolate and the reaction was heated on the steam bath for 1 hour,and then evaporated to dryness. The residue was dissolved in 25 ml. ofdichloromethane which was washed with 15 ml. of 5% potassium carbonatesolution, dried over anhydrous sodium sulfate and evaporated to dryness.The product was recrystallized twice from a mixture of methanol andethyl acetate to give product as white. rods, m.p. 326°-331°.

EXAMPLE 1036-(2-Fluorophenyl)-1-methyl-8-(N-methylacetamido)-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.8 g. (0.0024 g.) of8-acetamido-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 10 ml. of dry N,N-dimethylformamide under nitrogen was treated with0.13 g. (0.003 m) of 55% sodium hydride in mineral oil and after 30minutes the reaction mixture was cooled in an ice bath. To the stirredreaction 0.43 g. (0.003 m) of methyl iodide was added and after 18 hoursat room temperature the reaction mixture was poured into water.Filtration afforded the crude product which was recrystallized from amixture of ethyl acetate and ether to give product as off white prisms,m.p. 217°-223°.

EXAMPLE 1046-(2-Fluorophenyl)-1-methyl-8-methylamino-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.3 g. (0.000828 m) of6-(2-fluorophenyl)-1-methyl-8-(N-methylacetamido)-4H-imidazo[1,5-a][1,4]benzodiazepinein 10 ml. of methanol was treated with 3 ml. of concentratedhydrochloric acid and refluxed for 1 hour. The solution was made basicwith ammonium hydroxide and then partitioned between 50 ml. ofdichloromethane and 50 ml. of water. The organic phase was dried overanhydrous sodium sulfate and evaporated to dryness. The residual oil wasdissolved in 10 ml. of dichloromethane and filtered through Florisil. Itwas eluted with ether, ethyl acetate and finally ethyl acetatecontaining 5% methanol. This last mixture was evaporated, andcrystallized from a mixture of ethyl acetate and ether to give productas off white prisms, m.p. 255°-259°.

EXAMPLE 105(2-Fluorophenyl)-[2-(5-hydroxymethyl-2-methyl-1-imidazolyl)-5-nitrophenyl]methanone

A solution of 0.3 g. (0.00082 m) of8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepineisopropanolate in 0.5 ml. of sulfuric acid was treated with 4 g. of icefollowed by 0.2 g. (0.0029 m) of sodium nitrite. After 5 minutes thiswas added to a fresh solution prepared by adding 1 g. (0.00625 m) ofcopper sulfate in 10 ml. of water to 1 g. (0.00794 m) of sodium sulfitein 5ml. of water and then adding this to 8 g. (0.116 m) of sodiumnitrite in 40 ml. of water. After 15 minutes the reaction was warmed to35° for 5 minutes, made basic with 10% potassium carbonate solution andextracted with 100 ml. of dichloromethane. The organic layers werecombined, dried over anhydrous sodium sulfate, concentrated and appliedto a silica gel thick layer plate. This was developed in a mixture ofethyl acetate and ethanol (10/1), and the spot having an Rf of 0.5 wasscraped off. Crystallization from methanol and recrystallization from amixture of dichloromethane and ether gave product as off white prisms,m.p. 188°-192°.

EXAMPLE 106 A.(2-Fluorophenyl)[2-(2-methyl-5-dimethylaminomethyl-1-imidazolyl)-5-dimethylaminophenyl]methanonedipicrate.

A solution of 0.5 g. (0.00137 m) of8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepineisopropanolate in 20 ml. of formic acid and 5 ml. (0.062 m) of 37%formaldehyde was heated on the steam bath for 3 hours, and thenevaporated to dryness. The residue was dissolved in 50 ml. ofdichloromethane, which was washed with 15 ml. of 10% potassium carbonatesolution, dried over anhydrous sodium sulfate and concentrated. Theresidual oil was applied to and developed on 2 silica gel thick layerplates in a mixture of ethyl acetate and ethanol (7/1). The materialhaving an Rf of 0.4 was scraped off, washed with methanol, filtered andevaporated. The oil was dissolved in ether and 5 ml. of a 10% ethanolicsolution of picric acid was added. The precipitate was filtered andrecrystallized from a mixture of tetrahydrofuran and isopropanol to givethe product as yellow prisms, m.p. 228°-230°.

B. From8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepineisopropanolate

To a mixture of 0.1 g. (0.000273 m) and 5 ml. of water was added 1 ml.of concentrated hydrochloric acid. The reaction was cooled in an icebath and 0.15 g. (0.00217 m) of sodium nitrite was added slowly withstirring. After 1 hour the reaction mixture was poured into a solutionof 0.2 g. (0.00202 m) of cuprous chloride in 50 ml. of water which hadbeen heated to 70°. After 18 hours the reaction was made basic withsodium hydroxide, extracted with dichloromethane (2×50 ml.), dried overanhydrous sodium sulfate and evaporated to dryness. The residue wasdeveloped on a silica gel thick layer plate in a mixture of ethylacetate and methanol (10/1). The product which had an Rf of 0.7 asscraped off the plate, stirred with methanol and filtered. Evaporationand crystallization of the crude product from a mixture of ethyl acetateand ether gave product as white prisms, m.p. and mmp with an authenticsample 159°-166°.

EXAMPLE 107(2-Fluorophenyl)-[2-(5-hydroxymethyl-2-methyl-1-imidazolyl)-5-chlorophenyl]methanoneA. From8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 3 g. (0.00920 m) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 50 ml. of water and 0.5 ml. (0.4092 m) of concentrated sulfuric acidwas treated with 1.5 g. (0.0217 m) of sodium nitrite. After 18 hours anadditional 0.5 ml. of sulfuric acid and 1.5 g. of sodium nitrite wasadded, and after 10 minutes the reaction was made basic with 10 N sodiumhydroxide. The reaction mixture was extracted with 75 ml. ofdichloromethane, which was dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization of the residue from a mixture ofethyl acetate and ether gave the product as white prisms, m.p.165°-168°.

B. From5-aminomethyl-1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-2-methylimidazoledihydrochloride

A solution of 1 g. (0.00240 m) of5-aminomethyl-1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-2-methylimidazoledihydrochloride was dissolved in 20 ml of water and 1 g. (0.0145 m) ofsodium nitrite was added slowly with stirring in an ice bath. After 3hours the reaction was made basic with 10 N sodium hydroxide andextracted with 50 ml. of dichloromethane. The organic phase was driedover anhydrous sodium sulfate and evaporated to dryness. Crystallizationfrom ethyl acetate gave product as white prisms, m.p. and mmp with asample prepared as above 163°-166°.

EXAMPLE 1088-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.5 g. (0.00145 m) of(2-fluorophenyl)-[2-(5-hydroxymethyl-2-methyl-1-imidazolyl)-5-chlorophenyl]methanonein 25 ml. of dichloromethane was treated with 0.15 ml. (0.00155 m) ofphosphorous tribromide in an ice bath and after 1 hour at roomtemperature was poured into 50 ml. of liquid ammonia. After the ammoniahad evaporated the reaction was partitioned between 50 ml. ofdichloromethane and water. The organic phase was separated and driedover anhydrous sodium sulfate. The solution was concentrated and theresidue was applied to 2 silica gel thick layer plates which weredeveloped in a mixture of ethyl acetate/10% methanol.

The compound which had an Rf of 0.6 was scraped off, stirred withmethanol and filtered. The solution was treated with 0.1 g. (0.000962 m)of maleic acid and evaporated. The residual salt was crystallized from amixture of isopropanol and ether to give the maleate of the aboveproduct as white prisms, m.p. and mmp with an authentic sample112°-115°. * The base was obtained by partitioning the salt betweendichloromethane and water, adjusting the pH, separating the layers andevaporating the organic phase. Crystallization of the product from ethergave white prisms, m.p. and mmp with an authentic sample 154°-157°.

EXAMPLE 1098-Chloro-3-methoxymethyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 1.7 g. (0.005 m) of 8-chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 5 ml.of thionyl chloride was stirred at room temperature for 30 minutes. Thehydrochloride of8-chloro-3-chloromethyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinewas crystallized by addition of ethylacetate and ether. The collectedcrystals were partitioned betweeen methylene chloride and saturatedaqueous sodium bicarbonate solution. The organic phase was dried andevaporated. Crystallization of the residue from methylene chloride/etheryielded8-chloro-3-chloromethyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinewhich was heated to reflux for 10 minutes in 50 ml. of methanolcontaining 0.5 g. of sodium methoxide. The methanol was evaporated andthe residue was partitioned between methylene chloride and saturatedsodium bicarbonate solution. The organic phase was dried and evaporated.

Chromatography of this crude material over 30 g. of silica gel usingmethylene chloride/ethyl acetate 1:3 (v/v) yielded colorless crystalswith m.p. 163°-165° C., crystallized from ethylacetate/hexane.

EXAMPLE 1108-Chloro-6-(2-chlorophenyl)-3-cyanomethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 1 g. of8-chloro-3-chloromethyl-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,250 mg. of potassium cyanide and 20 ml. of dimethylformamide was heatedon the steambath with stirring for 3 hours. After dilution with water,the mixture was extracted with methylene chloride. The extracts werewashed with water, dried and evaporated. Chromatography of the residueon 30 g. of silica gel using methylene chloride/ethyl acetate 1:2 andcrystallization of the clean fractions from ether yielded final productwith m.p. 212°-214° C. The analytical sample was recrystallized fromethyl acetate/hexane, m.p. 215°-217° C.

EXAMPLE 1118-Chloro-3-(N-methoxyiminomethyl)-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Triethylamine, 2 ml., and 0.5 g. of methoxyamine hydrochloride was addedto a warm solution of 0.67 g. (0.002 m) of8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehydein 40 ml. of ethanol. The mixture was allowed to sit for 30 minutes. Thesolvent was partially evaporated and the product was crystallized bydiluting with water. The crystals were collected and dried to leavefinal product. The analytical sample was recrystallized from ether, m.p.193°-195° C.

EXAMPLE 1128-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehydedimethylhydrazone hemiethanolate

A mixture of 370 mg. (1 mmol) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde,10 ml. of ethanol and 0.5 ml. of 1,1-dimethylhydriazine was heated toreflux for 15 minutes. The solvent was evaporated and the residue wascrystallized from ethanol/water to yield light yellow crystals. Theanalytical sample was recrystallized from ethanol, m.p. 238°-242° C. Thecrystals contained according to nmr-spectrum and analysis 0.5 equivalentof ethanol.

EXAMPLE 1136-(2-Chlorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Phosphorus pentachloride, 1.1 g. (5.2 mmol), was added to a suspensionof 1.6 g. (4 mmol) of6-(2-chlorophenyl-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid in 100 ml. of methylene chloride cooled in ice-water.After stirring for 30 minutes in ice-water, a stream of ammonia wasintroduced until the mixture was alkaline and stirring was continued forone hour at room temperature. Water was added and the organic layer wasseparated, dried and evaporated. Crystallization of the residue frommethanol/ethyl acetate yielded yellowish crystals with mp>300°. Theanalytical sample was recrystallized from the same solvents.

EXAMPLE 1142-[(Benzoylamino)methoxycarbonylmethylene]-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine

A solution of 3.75 g. (0.01 m) of7-chloro-5-(2-fluorohenyl)-alphahydroxyimino-3H-1,4-benzodiazepine-2-aceticacid methyl ester in 300 ml. of tetrahydrofuran and 200 ml. of methanolwas hydrogenated at atmospheric pressure for 11/2 hour in presence ofone teaspoonful of Raney nickel. The catalyst was separated byfiltration over celite and the filtrate was evaporated under reducedpressure, at the end azeotropically with toluene. The residue wasdissolved in 20 ml. of pyridine and treated with 4 ml. ofbenzoylchloride. After sitting at room temperature for 15 minutes, thereaction mixture was partitioned between methylene chloride and 1 Nsodium hydroxide solution. The organic layer was dried and evaporated,at the end azeotropically with toluene. Crystallization of the residuefrom ether yielded final product with m.p. 210°-213° C. The analyticalsample was recrystallized from ethyl acetate/hexane, m.p. 217°-219° C.with softening at 150°-160° C.

EXAMPLE 1151-Methyl-8-(2-methyl-1,3-dioxolan-2-yl)-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate hemimethanolate

Hydrogenation of 5 g. (0.0137 m) of2,3-dihydro-7-(1-methyl-1,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-1H-1,4-benzodiazepinein 250 ml. of absolute ethanol in the presence of 1 teaspoon of Raneynickel for 3.5 hours yielded crude2-aminomethyl-2,3-dihydro-7-(1-methyl-1,3-dioxolan-2-yl)-5-phenyl-1H-1,4-benzodiazepine.To a solution of 4 g. (0.0119 m) of this compound in 75 ml. of absoluteethanol was added 0.7 g. (0.0037 m) of p-toluene sulfonic acid and 6 g.(0.037 m) of triethyl orthoacetate. The mixture was refluxed for 2hours, evaporated to dryness and the residue was dissolved in 50 ml. ofdichloromethane. This was washed with 25 ml. of dilute ammoniumhydroxide, dried over anydrous sodium sulfate and evaporated to givecrude3a,4-dihydro-1-methyl-8-(1-methyl-1,3-dioxolan-2-yl)-6-phenyl-3H-imidazo[1,5-a][1,4]benzodiazepineas an oil.

A solution containing 3.8 g. (0.0105 m) of this crude oil, and 18 g. ofactivated manganese dioxide in 100 ml. of toluene was refluxed andstirred for 2 hours using a Dean Stark trap. It was filtered and washedwith a mixture of 250 ml. of dichloromethane and 250 ml. oftetrahydrofuran. The filtrates were evaporated and dissolved in a smallamount of isopropanol and treated with 1.4 g. (0.0121 m) of maleic acidin ethanol. Ether was added and the precipitate was filtered andrecrystallized from a mixture of methanol and ether to give the aboveproduct as off white prisms, m.p. 179°-182°.

EXAMPLE 1168-Acetyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinedipicrate

A solution of 0.3 g. (0.1000607 m) of1-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinemaleate hemimethanolate in 10 ml. (0.01 m) of 1 N hydrochloric acid wasallowed to stand for 18 hours. A small amount of charcoal was added andthe reaction mixture was filtered. The solution was made basic withammonium hydroxide, extracted with 25 ml. of dichloromethane, dried overanhydrous sodium sulfate and evaporated to dryness. The residue wasdissolved in isopropanol and 0.35 g. (0.10015 m) of picric acid in 5 ml.of ethanol was added. The solution was evaporated and the residue wascrystallized from methanol. Recrystallization from a mixture oftetrahydrofuran and isopropanol gave the product as yellow prisms, m.p.225°-230°.

EXAMPLE 1178-(1-Hydroxyethyl)-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinedipicrate

A solution of 1 g. (0.00317 m) of8-acetyl-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepinedipicrate in 75 ml. of absolute ethanol was treated with 0.78 g. (0.0205m) of sodium borohydrode and after 18 hours the solution was evaporatedto dryness. The residue was acidified with dilute acetic acid, madebasic with ammonium hydroxide and the mixture was extracted with 75 ml.of dichloromethane. The organic layers were combined, dried overanhydrous sodium sulfate and evaporated to dryness. The oil thusobtained was dissolved in isopropanol and 1.6 g. (0.007 m) of picricacid in 20 ml. of ethanol was added. The precipitated salt was filteredand recrystallized twice from methanol to give the above product asyellow rods, m.p. 223°-225°.

EXAMPLE 1188-(1-Hydroxyethyl)-1-methyl-6-phenyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepinedipicrate

The filtrates from the reaction of Example 117 were concentrated andcrude product was filtered off. Recrystallization twice from a mixtureof tetrahydrofuran and methanol gave pure product as yellow rods, m.p.143°-145°.

EXAMPLE 1197-Cyano-5-(2-fluorophenyl)-2-bis-(morpholino)phosphinyloxy-3H-1,4-benzodiazepine

A solution of 10 g. (0.0358 m) of7-cyano-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one in 150ml. of dry tetrahydrofuran under argon was treated with 2.4 g. (0.0537m) of 54% sodium hydride and the reaction was stirred and refluxed for 1hour. This was cooled to 0° and 13.7 g. (0.0537 m) ofphosphorodimorpholidic chloride was added. After 18 hours the reactionmixture was filtered, concentrated to a small volume and ether wasadded. The precipitate was filtered and recrystallized from a mixture ofdichloromethane and ether to give product as white rods, m.p. 194°-197°.

EXAMPLE 120 Ethyl8-cyano-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate;and(Acetylamino)[7-cyano-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-yl]malonicacid diethyl ester

To 100 ml. of dry N,N-dimethylformamide under nitrogen was added 1.6 g.(0.036 m) of 54% sodium hydride, and 8.3 g. (0.038 m) ofacetamidodiethyl malonate was added with stirring. After 30 minutes 10g. (0.02 m) of7-Cyano-5-(2-fluorophenyl)-2-bis(morpholino)phosphinyloxy-3H-1,4-benzodiazepinewas added and after 64 hours the reaction was poured into ice watercontaining 4 ml. of acetic acid. This was filtered and the solid wasdissolved in 100 ml of dichloromethane, which was washed with 50 ml. ofwater, dried over anhydrous sodium sulfate and concentrated to a smallvolume. This solution was chromatographed over a column of Florisil andeluted with 2 l. of dichloromethane which was discarded. It was theneluted with 1 l. of a mixture of dichloromethane and ether (10/1) andthen with 2 l. of ether. The ether fraction was recrystallized twicefrom a mixture of dichloromethane and ether to give(acetylamino)[7-cyano-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-yl]malonicacid diethyl ester as white prisms, m.p. 138°-140°.

The column was eluted with 1.5 l. of a mixture of ethyl acetate andmethanol (10/1). The eluent was concentrated and the residue wascrystallized from ether. Recrystallization from a mixture ofdichloromethane and ether gave ethyl8-cyano-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylateas off white prisms, m.p. 272°-274°.

EXAMPLE 1218-Cyano-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.5 g. (0.00129 m) of ethyl8-cyano-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 100 ml. of ethanol and 10 ml. of water was treated with 0.14 g.(0.0026 m) of potassium hydroxide. After refluxing for 30 minutes thereaction was evaporated and 10 ml. of water was added. This wasacidified with acetic acid, filtered and extracted with 20 ml. ofdichloromethane, which was separated, dried and evaporated. About 0.2 g.of the hydrolyzed product was obtained from the filtration, and the sameamount was obtained from the extraction. This material was added to 3ml. of dry hexamethylphosphoramide and kept at 200°-205° for 30 minutesunder argon. It was cooled and 50 ml. of ice water and 1 ml. of ammoniumhydroxide were added. The solution was filtered and the filtrates wereextracted with 25 ml. of dichloromethane and evaporated to dryness.Water was added and the solution was filtered and the combinedprecipitates were dissolved in dichloromethane and developed on 2 silicagel thick layer plates in a solution of ethyl acetate containing 15%methanol. The silica gel containing the product was scraped off (Rf4-5), stirred with methanol and filtered. This was crystallized from amixture of isopropanol and ether to give the desired product as offwhite prisms, m.p. 198°-203°.

EXAMPLE 1227-Aminomethyl-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-onepicrate

A solution of 1 g. (0.00358 m) of7-cyano-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one washydrogenated in the presence of 0.5 teaspoon of Raney nickel for aperiod of 5 hours and was then allowed to stand for 18 hours morewithout stirring. The reaction mixture was filtered through Celite andconcentrated to a small volume. A solution of 0.9 g. (0.004 m) of picricacid in 10 ml. of ethanol was added. The precipitated salt was filteredand recrystallized twice from a mixture of tetrahydrofuran and methanolto give product as yellow prisms, m.p. 194°-198°.

EXAMPLE 1238-Chloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-5-(4-methylphenylsulfonyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

To a solution of 1.6 g. (5 mmoles) of8-chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 10 ml. of pyridine was added 1.2 g. (6 mmoles) of p-toluenesulfonylchloride. After standing at room temperature for 19 hours, the reactionmixture was diluted with water and extracted with methylene chloride.The organic extract was dried and concentrated in vacuo to dryness. Theresidue was crystallized from a mixture of methylene chloride, ether andgave product melting at 252°-253°. After recrystallizatin fromtetrahydrofuran the pure product formed yellow prisms with the samemelting point.

EXAMPLE 1245-Acetyl-8-chloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 1.5 g. of8-chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein a mixture of 10 ml. pyridine and 5 ml. of acetic anhydride was leftat room temperature for 18 hours. The reaction mixture was concentratedin vacuo to dryness. The residue was dissolved in methylene chloride andwashed with dilute potassium hydroxide. The organic layer was separated,dried and concentrated in vacuo to dryness. The residue was crystallizedfrom a mixture of methylene chloride, ether, petroleum ether and gaveproduct melting at 185°-186°. After recrystallization from methylenechloride the pure product formed colorless prisms melting at 186°-187°.

EXAMPLE 1258-Chloro-6-(2-fluorophenyl)-5,6-dihydro-5-nitroso-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

To a stirred solution of 1.6 g. of8-chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 10 ml. acetic acid was added slowly 0.4 g. of sodium nitrite. Afterstirring for 1.5 hours the reaction mixture was poured into ice water,made alkaline with 50% potassium hydroxide and extracted with methylenechloride. The organic extract was separated, dried and concentrated invacuo to dryness. The residue was crystallized from a mixture ofmethylene chloride, ether and gave product melting at 238°-240°. Afterrecrystallization from the same solvent mixture the pure product formedcolorless prisms with unchanged melting point.

EXAMPLE 1268-Chloro-6-(2-fluorophenyl)-5,6-dihydro-1,5-dimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine

To a solution of 1.6 g. (5 mmoles) of8-chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 5 ml. of formic acid was added 2.4 ml. of 37% formaldehyde. Thereaction mixture was heated on the steambath for 5 hours, then pouredinto ice water, made alkaline with 50% potassium hydroxide and extractedwith methylene chloride. The organic extract was separated, dried andconcentrated in vacuo to dryness. The residue was crystallized fromether and gave product melting at 156°-158°. After recrystallizationfrom ether the pure product formed colorless prisms melting at158°-159°.

EXAMPLE 1275-Allyl-8-chloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

To a stirred solution of 0.98 g. (3 mmoles) of8-chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 25 ml. of dry dimethylformamide was added 0.2 g. (4.3 mmoles) of 57%sodium hydride. After 15 minutes 0.4 ml. (4.3 mmoles) of allylbromidewas added and the stirring continued for 6 hours. The reaction mixturewas poured into ice water and extracted with a mixture of ether andpetroleum ether. The organic layer was separated, dried and concentratedin vacuo to dryness. The residue was crystallized from a mixture ofether/petroleum ether and gave product melting at 140°-145°. Afterrecrystallization from ether the pure product formed colorless prisms,melting at 153°-154°.

EXAMPLE 1288-Chloro-6-(2-fluorophenyl)-5,6-dihydro-5-hydroxy-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

To a stirred solution of 1.2 g. (3.5 mmoles) of8-chloro-6-(2-fluorophenyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide in 120 ml. of ethanol was added slowly 1.2 g. (31 mmoles) ofsodium borohydride. After stirring for 4.5 hours at room temperature thereaction mixture was diluted with about 175 ml. of water and producedmelting at 246°-248° was separated by filtration. Afterrecrystallization from a mixture of methylene chloride/ether, the pureproduct formed colorless needles melting at 251°-252°.

EXAMPLE 1298-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepineA. From8-chloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-5-(4-methylphenylsulfonyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

To a stirred solution of 2.4 g. (5 mmoles) of8-chloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-5-(4-methylphenylsulfonyl)-4H-imidazo[1,5-a][1,4]benzodiazepinein 120 ml. of dry tetrahydrofuran was added 1.1 g. of potassiumtert-butoxide. After stirring at room temperature for 2 hours thereaction mixture was poured into ice water and extracted with a 50%mixture of ether and petroleum ether. The organic extract was dried andconcentrated in vacuo to dryness. The residue was crystallized from amixture of ether, petroleum ether and gave product melting at 152°-153°.The mixed melting point with an authentic sample gave no depession.

B. From8-chloro-6-(2-fluorophenyl)-5,6-dihydro-5-nitroso-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

To a stirred solution of 1.7 g. (4.7 mmoles) of8-chloro-6-(2-fluorophenyl)5,6-dihydro-5-nitroso-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 25 ml. of dry dimethylformamide was added 0.6 g. (5 mmoles) ofpotassium t-butoxide. After 5 minutes the reaction mixture was pouredinto ice water and extracted with methylene chloride. The organic layerwas separated, dried and concentrated in vacuo to dryness. The residuedissolved in methylene chloride was filtered over 12 g. Woelm I aluminaand the filter bed washed with the same solvent. The filtrate (ca. 120ml.) was concentrated in vacuo to dryness. The residue was crystallizedfrom ether and gave product melting at 139°-145°. Afterrecrystallization from ether the product melted at 153°-155° and a mixedmelting point with an authentic sample gave no depression.

C. From 8-chloro-6-(2-fluorophenyl)-5,6-dihydro-5-hydroxy-1-methyl-4H-imidzo[1,5-a][1,4]benzodiazepine

A solution of 0.3 g. of8-chloro-6(2-fluorophenyl)-5,6-dihydro-5-hydroxy-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein a mixture of 10 ml. of pyridine and 2 ml. of acetic anhydride wasleft at room temperature for 19 hours. The reaction mixture wasconcentrated in vacuo to dryness. The residue was dissolved in 20 ml. ofmethanol and 0.2 g. of sodium methoxide added. After standing at roomtemperature for 45 minutes, the reaction mixture was concentrated invacuo to dryness. The residue was partitioned between methylene chlorideand water. The organic layer was separated, dried and concentrated invacuo to dryness. The residue was crystallized from a methylenechloride/ether mixture and gave starting material melting at 255°-256°.Concentration of the filtrate and crystallization of the residue fromether gave the desired product melting at 158°-160°. The mixed meltingpoint with an authentic sample gave no depression.

EXAMPLE 1302-Aminomethyl-7-chloro-2,3,4,5-tetrahydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine

To a stirred solution of 27.8 g. (92 mmoles) ofDL-2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinein a mixture of 450 ml. of methylene chloride and 300 ml. of acetic acidwas added slowly 27.8 g. of zinc dust. After stirring at roomtemperature for 4 hours the reaction mixture was filtered over Celite.The filtrate was diluted with ice water, made alkaline with 50%potassium hydroxide solution and extracted with methylene chloride. Theorganic extract was separated, dried and concentrated in vacuo todryness. The residue was crystallized from ether and gave productmelting at 119°-120°. After recrystallization from ether the pureproduct formed slightly yellow prisms melting at 127°-128°.

The hydrochloride was prepared by treating a solution of the base inisopropanol with an excess of concentrated hydrochloric acid. Afterrecrystallization of the salt from a mixture of water and isopropanolthe pure product formed slightly yellow needles melting at 268°-271°.

EXAMPLE 1318-Chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine(Isomer A) Method A. From rac.2-aminomethyl-7-chloro-2,3,4,5-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 3 g. (10 mmoles) of2-aminomethyl-7-chloro-2,3,4,5-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepinein a mixture of 30 ml. of xylene and 10 ml. of triethylorthoacetate(97%) was refluxed for 4 hours. The reaction mixture was diluted withether and extracted with dilute ice cold hydrochloric acid. The acidextract was made alkaline with dilute potassium hydroxide and extractedwith methylene chloride. The organic layer was separated, dried andconcentrated in vacuo to dryness. The residue was crystallized fromether and gave product melting at 187°-189°. After recrystallizationfrom a mixture of methylene chloride and ether the pure product formedslightly yellow prisms melting at 189°-190°.

Method B. From8-chloro-3a,4-dihydro-6-(6-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]-benzodiazepine

To a stirred solution of 2.5 g. of8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5a][1,4]benzodiazepinein a mixture of 100 ml. methylene chloride and 25 ml. of acetic acid wasadded slowly 2.5 g. of zinc dust. After stirring at room temperature for4 hours, the reaction mixture was filtered over Celite. The filtrate wasdiluted with ice water, made alkaline with 50% potassium hydroxide andextracted with methylene chloride. The organic extract was separated,dried and concentrated in vacuo to dryness. The residue was crystallizedfrom ether and gave product which was identical with the productprepared above, m.p. and mmp 189°-190°.

EXAMPLE 1328-Chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine(Isomer B)

A solution of 3.2 g. (10 mmoles) of8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepinein 50 ml. acetic acid and 10 ml. of water was hydrogenated at roomtemperature and atmospheric pressure in the presence of 0.4 g. ofprehydrogenated platinum oxide. After 15 minutes, 10 mmoles of hydrogenwas absorbed. The catalyst was separated by filtration and the filtrateconcentrated in vacuo to dryness. The residue was dissolved in methylenechloride and washed with an excess of ice cold dilute sodium carbonate.The organic layer was separated, dried and concentrated in vacuo todryness. The residue was crystallized from a mixture of ether/petroleumether and gave product melting at 108°-110°. After recrystallizationfrom ether the pure product formed colorless prisms melting at110°-112°.

EXAMPLE 1338-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 2.9 g. of8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine,90 ml. of toluene and 15 g. of activated manganese dioxide was stirredand refluxed for 2 hours. The reaction was filtered over Hyflo and thefiltrate concentrated in vacuo to dryness. The residue was crystallizedfrom ether and gave product which gave no melting point depression withan authentic sample.

EXAMPLE 1342-Chloro-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H,11H-imidazo[1,5-a]oxazolo[3,2-d][1,4]benzodiazepine,and maleate

A solution of 5 g. (0.00153 m) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 75 ml. of dry ethylene dichloride was cooled in an ice bath and 5 g.(0.0352 m) of boron trifluoride etherate was added. After 10 minutes asolution of 4 g. (0.092 m) of ethylene oxide in 5 ml. of ethylenedichloride was added with stirring. After 1 hour at room temperature themixture was made basic with a solution of potassium carbonate in water.The organic layer was separated, dried over anhydrous sodium sulfate,and evaporated. The residue was dissolved in 50 ml. of dichloromethaneand filtered through 150 g. of Florisil. The Florisil was eluted with750 ml. of dichloromethane and then with 750 ml. of ether.

The dichloromethane solution was evaporated and partitioned between 100ml. of ether and 100 ml. of 0.5 N hydrochloric acid. The acid layer wasseparated, made basic with ammonium hydroxide and extracted with 100 ml.of dichloromethane which was dried and evaporated. The oil was dissolvedin 15 ml. of isopropanol and 0.8 g. (0.0069 m) of maleic acid was added.The solution was warmed on the steam bath for 5 minutes, cooled andether was added. The precipitate was filtered, and recrystallized from amixture of methanol and ether to give the maleate of the above productas white prisms, m.p. 195°-200°.

The ether solution from the Florisil was concentrated, filtered andrecrystallized from ether to give the base as white prisms, m.p.178°-180°.

EXAMPLE 1357-Chloro-2,3-dihydro-5-(2-fluorophenyl)-2-trifluoroacetaminomethyl-1H-1,4-benzodiazepine

A solution of 2.8 g. (0.00932 m) ofDL-2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinein 40 ml. of dichloromethane was treated with 2.5 g. (0.0119 m) oftrifluoroacetic acid anhydride and after 5 minutes it was washed with 15ml. of a 10% potassium carbonate solution, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was crystallized fromdichloromethane and was recrystallized from a mixture of dichloromethaneand hexane to give the above product as pale yellow prisms, m.p.140°-143°.

EXAMPLE 1365-(2-Fluorophenyl)-7-iodo-2-bis-(morpholino)-phosphinyloxy-3H-1,4-benzodiazepine

To a solution of 10 g. (0.0264 m) of5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one in 140ml. of dry tetrahydrofuran was added 1.8 g. (0.039 m) of 54% sodiumhydride under argon with stirring. The reaction was refluxed for 1 hour,cooled to 0°, and 10.8 g. (0.0422 m) of phosphorodimorpholidic chloridewas added. After 18 hours the solution was filtered, concentrated to asmall volume and ether was added. The product was filtered andrecrystallized from a mixture of dichloromethane and ether to giveproduct as white plates, m.p. 104°-112°.

EXAMPLE 1372,3-Dihydro-5-(2-fluorophenyl)-7-iodo-2-nitromethylene-1H-1,4-benzodiazepine

A solution of 27 g. (0.443 m) of nitromethane in 450 ml. of dry dimethylsulfoxide was cooled to 0° under argon and then 5.4 g. (0.119 m) of 54%sodium hydride was added with stirring. After 2 hours at roomtemperature the mixture was cooled to 0° and 39.5 g. (0.066 m) of5-(2-fluorophenyl)-7-iodo-2-bis(morpholino)-phosphinyloxy-3H-1,4-benzodiazepinewas added all at once. The reaction was stirred for 18 hours and thenpoured into 3 l. of ice and water, which contained 15 ml. of aceticacid. This was filtered, the precipitate was dissolved in 700 ml. ofdichloromethane which was then washed with 300 ml. of water, dried overanhydrous sodium sulfate and evaporated to dryness. The residue wascrystallized and recrystallized from a mixture of dichloromethane andether to give product as yellow prisms, m.p. 214°-216°.

EXAMPLE 1387-Chloro-5-(2-chlorophenyl)-2-dimethoxymalonylidene-1,3-dihydro-2H-1,4-benzodiazepine

7-Chloro-5-(2-chlorophenyl)-2-[bis(morpholino)phosphinyloxy]3H-1,4-benzodiazepine,5.3 g. (0.01 m) was added to a mixture of 10 ml. of dimethyl malonate,20 ml. of dimethylformamide and 2.2 g. (0.02 m) of potassium t-butoxidewhich had been stirred at room temperature for 5 minutes under nitrogen.The reaction mixture was then stirred and heated on the steam bath for15 minutes. After addition of 1.5 ml. of glacial acetic acid the productwas crystallized by gradually diluting with water. The precipitatedcrystals were collected, washed with water and dried in vacuo to yieldproduct which was recrystallized for analysis from ethyl acetate, m.p.205°-207°.

EXAMPLE 1397-Chloro-5-(2-chlorophenyl)-2,3-dihydro-2-[(methoxycarbonyl)methylene]-1H-1,4-benzodiazepine

A mixture of 12.6 g. (0.03 m) of7-chloro-5-(2-chlorophenyl)-2-dimethoxymalonylidene-1,3-dihydro-2H-1,4-benzodiazepine,300 ml. of methanol and 2.1 g. (0.0375 m) of potassium hydroxide washeated to reflux under nitrogen for 41/2 hours, 200 ml. of methanol weredistilled off and the residue was diluted with water. The separatedcrystals were collected, washed with water and dried to yield productwith m.p. 154°-158°. For analysis it was recrystallized from methylenechloride/methanol, m.p. 158°-159°.

EXAMPLE 1407-Chloro-5-(2-chlorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid, methyl ester

Sodium nitrite, 2.2 g. (0.031 m) was added in portions over 5 minutes toa stirred solution of 7.2 g. (0.02 m) of7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2-[methoxycarbonyl)methylene]-1H-1,4-benzodiazepinein 75 ml. of glacial acetic acid. After stirring for additional 15minutes, the mixture was diluted with 100 ml. of water and theprecipitated crystals were collected, washed with water, methanol andether to leave crude product which was recrystallized fromtetrahydrofuran/methanol to yield light yellow crystals with m.p.223°-225° dec.

EXAMPLE 141 Methyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A solution of 3.9 g. (0.01 m) of7-chloro-5-(2-chlorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid, methyl ester in 100 ml. of tetrahydrofuran and 50 ml. of methanolwas hydrogenated in the presence of 2 teaspoonsful of Raney nickel for11/2 hours at atmospheric pressure. The catalyst was removed byfltration and the filtrate was evaporated, and the end azeotropicallywith toluene. The residue was dissolved in 20 ml. of ethanol.Triethylorthoacetate, 3 ml., and 0.2 ml. of ethanolic hydrogen chloride(10%) was added and the mixture was heated to reflux for 15 minutes, andthen evaporated to dryness. The residue was partitioned betweenmethylene chloride and saturated aqueous bicarbonate solution. Theorganic layer was separated, drid over sodium sulfate and evaporated.Crystallizatin of the residue from methylene chloride/ether yieldedcrystals with m.p. 225°-227°. The analytic sample was recrystallizedfrom 2-propanol and ethyl acetate, m.p. 228°-230°.

EXAMPLE 144

Acetylamino[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]malonicacid, diethyl ester

A stirred suspension of 7.8 g. (0.174 m) of a 54% mineral oil dispersionof sodium hydride in 480 ml. of dimethylformamide was treatedportionwise under argon with 30 g. (0.18 m) of diethylacetamidomalonate. When the reaction had abated (ca. 30 minutes), 48 g.(0.096 m) of7-chloro-5-(2-fluorophenyl)-2-[bis(morpholino)phosphinyloxy]-3H-1,4-benzodiazepinewas added in one portion. Stirring was continued at room temperature for5 hours, under argon. The dark mixture was poured, with stirring, into amixture of ice and glacial acetic acid to give a light tan solid whichwas filtered, washed with water and partially air dried on the funnel.The damp solid was dissolved in methylene chloride. After separating thewater layer the solution was dried over sodium sulfate, filtered andevaporated under reduced pressure to give a tan foam. The foam wasdissolved in isopropanol (4 ml/g.) with stirring and kept at roomtemperature for 1 hour with occasional scratching to give off-whitecrystals. An equal volume of petroleum ether (30°-60°) was added and themixture was kept at room temperature an additional 30 minutes beforefiltration. Washing with petroleum ether and air drying on the funnelyielded product, m.p. 150°-180°. Recrystallization of a sample fromethanol (10 ml/g.) raised the melting point to 185°-195° with previoussoftening.

EXAMPLE 1425-(2-Fluorophenyl)-2-[bis(morpholino)phosphinyloxy]-7-nitro-3H-1,4-benzodiazepine

A stirred solution of 29.9 g. (0.1 m) of1,3-dihydro-5-(2-fluorophenyl)-7-nitro-2H-1,4-benzodiazepin-2-one in 500ml. of dry tetrahydrofuran was treated under argon portionwise with 5.5g. (0.125 m) of a 54% mineral oil dispersion of sodium hydride andstirring was continued for 1 hour longer. Dimorpholinophosphinicchloride (38 g., 0.15 m) was added to the dark solution in one portionand stirring under argon was continued for 8 hours. The resultant darkmixture was filtered over filter aid and concentrated in vacuo at 50° togive a dark gum. When the dark gum was stirred at room temperature in 75ml. of ethyl acetate, crystallization occurred to give a paste. Aftercooling in an ice bath for 30 minutes the mixture was filtered and thelight tan solid was washed 3 times with 35 ml. portions of 2:1ether/ethyl acetate and finally with ether. Air drying on the funnelyielded nearly pure product. Recrystallization from 15 fold amount ofethyl acetate gave off-white needles, m.p. 169°-172°.

EXAMPLE 1437-Bromo-2-[bis(morpholino)phosphinyloxy]-5-(2-pyridyl)-3H-1,4-benzodiazepine

Fifty-four percent sodium hydride in mineral oil dispersion (11 g., 0.25m) was added in portions to a stirred solution of 63.2 g. (0.2 m) of7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 1 l. oftetrahydrofuran under argon. After refluxing on a steam bath for 1 hour,the solution was cooled to room temperature and treated with 76.2 g.(0.3 m) of dimorpholinophosphinic chloride portionwise. Stirring at roomtemperature was continued for 5 hours. The dark mixture was filteredthrough Celite. Concentration of the filtrate in vacuo and boiling thedark residue with ether gave tan crystals. A sample was recrystallizedby dissolving it in 2 ml. of methylene chloride, filtering, dilutingwith 10 ml. of ethyl acetate and cooling in an ice bath to give lighttan plates. m.p. 180°-182° (dec.).

EXAMPLE 145Acetylamino[7-chloro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]malonicacid, diethyl ester

A stirred suspension of 4 g. (0.09 m) of a 54% mineral oil dispersion ofsodium hydride in 315 ml. of dimethylformamide under argon was treafedwith 21 g. (0.096 m) diethyl acetamidomalonate in several portions.Stirring at room temperature was continued for 30 mimutes and then 31.4g. (0.06 m) of7-chloro-5-(2-chlorophenyl)-2-[bis(morpholino)phosphinyloxy]-3H-1,4-benzodiazepinewas added in one portion. After stirring an additional 7 hours at roomtemperature the dark mixture was poured over ice and acetic acid withstirring and diluted with water (ca. 2 l.) to give a cream coloredsolid. The solid was filtered, washed with water and air dried on thefunnel to give product. The dried solid was stirred with a small amountof 2-propanol while warming on a steam bath until solution occurred.Cooling to room temperature gave an off-white solid. Recrystallizationof a sample from 8-fold amount of ethanol gave off-white microneedles,m.p. 153°-155°.

EXAMPLE 146 Acetylamino[7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]malonic acid, diethylester

A stirred suspension of 54% sodium hydride in mineral oil dispersion(3.35 g., 0.075 m) in 267 ml. of dimethylformamide was treated underargon with 17.5 g. (0.08 m) of diethyl acetamidomalonate in severalportions. The mixture was stirred at room temperature 30 minutes longerand then treated with 26.7 g. (0.05 m) of7-bromo-2-[bis(morpholino)phosphinyloxy]-5-(2-pyridyl)-3H-1,4-benzodiazepinein one portion. Stirring under argon at room temperature was continuedfor 7 hours. The dark mixture was poured over ice-acetic acid anddiluted with water to give a greenish yellow solid. The solid wasfiltered, washed with water and air dried on the funnel to yieldproduct. About 7 g of the solid was chromatographed over silica gel andeluted with ethyl acetate to give amorphous solid which showed one spoton tlc (ethyl acetate); Rf 0.5. When stirred with a small amount ofisopropanol, the solid crystallized. Recrystallization of a sample fromisopropanol gave light tan plates, m.p. 178°-180°.

EXAMPLE 1472-[(Acetylamino)ethoxycarbonylmethylene]-7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepinemaleate

A stirred solution of sodium ethoxide (prepared from 0.2 g., 0.01 g.atm. of sodium metal in 25 ml. of absolute ethanol) was treated with 2.4g. (0.005 m) of acetylamino[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]malonic acid,diethyl ester, protected by a drying tube and stirred 5 hours longer atroom temperature. The precipitated yellow solid was collected byfiltration, washed successively with ethanol and ether and air dried togive product. The solid was partitioned between water and methylenechloride, acidified with acetic acid and extracted again with methylenechloride. After washing with dilute ammonium hydroxide solution themethylene chloride extract was dried over sodium sulfate and evaporatedin vacuo to give a tan foam. A solution of 1. g. (0.0024 m) of the basein 25 ml. of ether was mixed with a solution of 0.56 g. (0.0048 m) ofmaleic acid in 25 ml. of ether and kept at room temperature. Orangecrystals were obtained after several minutes with occasional scratching.The crystals were collected by filtration, washed with ether and airdried to yield product, m.p. ca. 150°. Recrystallization from 30 ml. ofethyl acetate after concentrating to 1/2 volume and seeding gave orangeprisms, m.p. 149°-151°.

EXAMPLE 1482-[(Acetylamino)ethoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepinemaleate

A solution of sodium ethylate was prepared by dissolving 0.8 g. (0.04 g.atm.) of sodium metal in 50 ml. of absolute ethanol and protected by adrying tube.Acetylamino[7-chloro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]malonicacid, diethyl ester (10.1 g., 0.02 m) was added in one portion to thestirred solution and stirring in a dry atmosphere was continued at roomtemperature for 5 hours. The resulting mixture was acidified with aceticacid and concentrated in vacuo. The residue was partitioned betweendilute ammonium hydroxide and methylene chloride. After separating thelayers, the organic layer was dried over sodium sulfate and evaporatedat reduced pressure to give a tan, amorphous solid. The solid wasdissolved in 75 ml. of anhydrous ether and added to a warm solution of 4g. of maleic acid in 200 ml. of ether. After decanting from a smallamount of brown gum, the solution was concentrated on a steam bath toabout 100 ml. Cooling at room temperature with occasional scratchinggave crystallization after about 30 minutes. When crystallization wascomplete, the orange crystals were filtered, washed with ether and airdried on the funnel to give product. Recrystallization of a small samplefrom ethyl acetate (5 ml/g) gave yellow microneedles, m.p. 139°-142°(dec.).

EXAMPLE 149 Ethyl6-(2-fluorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate

A stirred suspension of 0.85 g. (0.018 m) of a 54% mineral oildispersion of sodium hydride in 55 ml. of dry dimethylformamide wastreated with 3.5 g. (0.016 m) of diethyl acetamidomalonate in severalportions under argon. After stirring for 30 minutes, 5.2 g. (0.01 m) of5-(2-fluorophenyl)-2-[bis(morpholino)phosphinyloxy]-7-nitro-3H-1,4-benzodiazepine was added in one portionand stirring under argon was continued for 7 hours longer. The darkmixture was poured into a stirred mixture of ice and acetic acid anddiluted with water to give a brownish yellow solid. The solid was washedwith water and air dried on the funnel to give product. Tlc (ethylacetate) showed 3 yellow spots with Rf 0.8, 0.5 and 0.25. Chromatographyover silica gel using ethyl acetate as eluent gave the desired productwith Rf of 0.25 as a brownish yellow solid. Recrystallization of thesample from ethyl acetate (5 ml/g) by dissolving in hot ethyl acetateand cooling in an ice bath gave yellow prisms, m.p. 231°-233°.

EXAMPLE 150 Ethyl8-chloro-5-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate

Crude2-[(acetylamino)ethoxycarbonylmethylene]-7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine(6.3 g., 0.015 m) which was prepared from the maleate by basifying withammonia, extracting with methylene chloride and evaporating in vacuo,was dissolved in 35 ml. of hexamethylphosphoramide (HMPA) and heated,with stirring at 200°-210° for 5 minutes. The dark solution was cooledand poured into ice water to give a tan solid. The solid was filtered,washed with water and partially air dried on the funnel. The damp solidwas dissolved in methylene chloride, dried over sodium sulfate andevaporated at reduced pressure to give product as tan foam.Recrystallization of 1 g. of the foam from 5 ml. of ethyl acetate and 5ml. of petroleum ether (30°-60° C.) gave the product as light tanprisms, which melted at 176°-179°, slowly resolidified and melted againat 195°-198°.

EXAMPLE 151 Ethyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A solution of 3.2 g. (0.0073 m) of2-[(acetylamino)ethoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepinein 15 ml. of hexamethylphosphoramide was stirred under nitrogen andheated at 200°-210° for 10 minutes. After cooling to room temperaturethe solution was poured into ice water and diluted with more water untilprecipitation was complete. The tan solid was filtered, washed withwater and air dried on the funnel to give product. When stirred withethyl acetate (2 ml/g) the solid dissolved and immediatelyrercrystallized. The tan solid was filtered, washed with 1:1 ethylacetate-petroleum ether and air dried to give the above named product.Recrystallization of a sample from methylene chloride-ethyl acetatesolution by removal of the methylene chloride by boiling gave off-whiteneedles, m.p. 214°-215°.

EXAMPLE 152 Ethyl8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylate

Diethyl acetamidomalonate, 43 g. (0.2 m) was added to a suspension of 10g. (0.2 m) of a dispersion (50%) of sodium hydride in mineral oil in 500ml. of dry dimethylformamide. This mixture was stirred under argon for 1hour at room temperature and for 20 minutes with heating on the steambath.7-Bromo-2[bis(morpholino)phosphinyloxy]-5-(2-pyridyl)-3H-1,4-benzodiazepine,53.4 g. (0.1 m) was then added to the reaction mixture brought back toroom temperature. After stirring for 1 hour at room temperature, it wasagain heated on the steam bath for 2 hours. The cooled solution waspartitioned between water and methylene chloride/ether. The organicphase was separated, washed with water, dried and evaporated. Theresidue was crystallized with seeding from ethyl acetate/ether to giveproduct as off-white crystals with m.p. 240°-243°. Seeds were obtainedby chromatographic purification over 30 fold amount of silica gel using5% (v/v) methanol in ethyl acetate. The analytical sample wasrecrystallized from ethyl acetate, m.p. 243°-244°.

EXAMPLE 153 Ethyl6-(2-chlorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Diethyl acetamidomalonate, 43 g. (0.2 m) was added to a suspension of 10g. (0.2 m) of sodium hydride (50% in mineral oil) in 500 ml. of drydimethylformamide. The mixture was heated to 50° for 30 minutes underargon. After addition of 53 g. (0.1 m) of5-(2-chlorophenyl)-2-[bis(morpholino)phosphinyloxy]-7-nitro-3H-1,4-benzodiazepine,the reaction mixture was heated on the steambath for 1 hour. The cooledbrown mixture was partitioned between water and methylenechloride/ether. The organic phase was washed with water, dried andevaporated. The residue was chromatographed over 1 kg. of silica gelusing ethyl acetate. The clean fractions of product were combined andevaporated. Crystallization of the residue from methylene chloride/etheryielded product as light yellow crystals with m.p. 233°-234°. Theanalytical sample was recrystallized from ethyl acetate, m.p. 234°-235°.

EXAMPLE 154 Ethyl1-methyl-8-nitro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Sodium hydride dispersion (50% in mineral oil), 6 g. (0.125 m), wasadded to a solution of 28.1 g. (0.1 m) of1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzo-diazepin-2-one in 300 ml. ofdry tetrahydrofuran. After stirring for 1 hour at room temperature 30.2g. (0.12 m) of dimorpholinophosphinic chloride was added and stirringwas continued for 4 hours. The product was crystallized by addition ofwater and ether. The precipitate was collected and dissolved inmethylene chloride. The solution was dried and evaporated and theresidue was crystallized from ethyl acetate to yield crude7-nitro-2-[bis(morpholino)phosphinyloxy]-5-phenyl-3H-1,4-benzodiazepinewith m.p. 208°-209°.

Part of this material was added to a mixture of 8.6 g. (0.04 m) ofdiethyl acetaminomalonate, 2 g. (0.04 m) of sodium hydride suspension(50% in mineral oil) and 75 ml. of dimethylformamide which had beenheated at 40° for 30 minutes. After addition the reaction mixture washeated for 30 minutes on the steambath and was then partitioned betweenwater and ether. The organic phase was washed with water, dried andevaporated. The residue was chromatographed over 250 g. of silica gelusing ethyl acetate. The combined clean fractions of product wereevaporated and the residue was crystallized from methylenechloride/ether to yield product as off-white crystals with m.p.240°-241°. The analytical sample was recrystallized from ethyl acetate.

EXAMPLE 1551-Methyl-8-nitro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid

A mixture of 1.95 g. (5 mmol) of ethyl1-methyl-8-nitro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,50 ml. of methanol, 0.56 g. (0.01 m) of potassium hydroxide and 2 ml. ofwater was heated to reflux under nitrogen for 3 hours. After partialevaporation of the solvent the residue was acidified with 2 ml. ofglacial acetic acid and was partitioned between methylene chloridecontaining 10% (v/v) of ethanol and water. The organic phase was driedand evaporated. Crystallization of the residue from ethylacetate/methanol yielded product as straw colored crystals which wererecrystallized from the same solvents for analysis, m.p. 240°-243° dec.

EXAMPLE 1566-(2-Chlorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine3-carboxylic acid

A mixture of 4.25 g. (0.01 m) of ethyl6-(2-chlorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,100 ml. of methanol, 1.12 g. (0.02 m) of potassium hydroxide and 4 ml.of water was heated to reflux under nitrogen for 3 hours. The bulk ofthe methanol was evaporated and the residue was partitioned betweenwater and ether. The aqueous phase was washed with ether, acidified withacetic acid and extracted with methylene chloride. The extracts weredried and evaporated. Crystallization of the residue from methylenechloride/ethyl acetate yielded yellow product with m.p. 272°-274° dec.The analytical sample was recrystallized from methanol/ethyl acetate,m.p. 274°-276° dec.

EXAMPLE 1578-Bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid

A mixture of 2.15 g. (5 mmol) of ethyl8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,50 ml. of methanol, 0.84 g. (15 mmol) of potassium hydroxide and 2.5 ml.of water was heated to reflux for 5 hours. The bulk of the methanol wasevaporated and the residue was partitioned between water and ether. Theaqueous phase was acidified with acetic acid and extracted withmethylene chloride. The extracts were dried and evaporated.Crystallization of the residue from methylene chloride/ethyl acetategave product as colorless crystals which were recrystallized frommethanol for analysis, m.p. 245°-250° dec. with previous sintering.

EXAMPLE 1581-Methyl-8-nitro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate,hemi-ethyl acetate

A suspension of 1.2 g. of1-methyl-8-nitro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 15 ml. of hexamethyl phosphoric acid triamide was heated toreflux for 3 minutes. The cooled solution was partitioned betweenmethylene chloride/ether and aqueous sodium bicarbonate solution. Theorganic phase was washed with bicarbonate solution, dried andevaporated. The residue was chromatographed over 30 g. of silica gelusing 3% (v/v) of ethanol in methylene chloride. Crystallization of theclean fractions from ether/methylene chloride/ethyl acetate yielded1-methyl-8-nitro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine with m.p.168°-170°. It was converted to the maleate salt which crystallized fromethyl acetate with 0.5 m of solvent, m.p. 125°-128° dec.

EXAMPLE 159 6-(2-Chlorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine maleate

A mixture of 1.5 g. of6-(2-chlorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid and 10 ml. of ethylene glycol was heated to reflux for 1 hour. Thereaction mixture was then partitioned between methylene chloride/tolueneand saturated aqueous sodium bicarbonate solution. The organic phase waswashed with water, dried and evaporated. The residue was dissolved in 10ml. of 2-propanol and treated with 0.6 g. of maleic acid. The saltcrystallized upon addition of ether to the warm solution. It wascollected, washed with 2 -propanol and ether to yield product as tancrystals which were recrystallized from 2-propanol for analysis, m.p.150°-152°. The free base liberated from this salt was crystallized fromethyl acetate/hexane, m.p. 170°-173°.

EXAMPLE 1608-Bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 1.3 g. of8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 20 ml. of ethylene glycol was heated to reflux for 1 hour. Thereaction mixture was partitioned between water and methylenechloride/toluene. The organic phase was washed with saturated sodiumbicarbonate solution, dried and evaporated. Crystallization of theresidue from ether/2-propanol gave product as tan crystals. Theanalytical sample was recrystallized from ethyl acetate/hexane, m.p.189°-190°.

EXAMPLE 1618-Chloro-6-(2-chlorophenyl)-3-hydroxymethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 1.2 g. (3 mmol) of methyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 10 ml. of tetrahydrofuran was added to a suspension of 0.4 g. (10mmol) of lithium aluminum hydride in 30 ml. of ether cooled to 10°.Following the addition, the mixture was stirred at room temperature for10 minutes and hydrolyzed by addition of 2 ml. of water. The inorganicmaterial was filtered off and the filtrate was evaporated.Crystallization of the residue from methylene chloride/ether yieldedproduct with m.p. 215°-217°. The analytical sample was recrystallizedfrom tetrahydrofuran/hexane, m.p. 217°-128°.

EXAMPLE 1628-Chloro-N,N-diethyl-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Phosphorus pentachloride, 1.25 g. (0.006 m) was added to a suspension of1.85 g. (0.005 m) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 250 ml. of methylene chloride. After stirring for 30 minutes inan ice bath, 15 ml. of diethylamine was added followed by 100 ml. of 10%aqueous sodium carbonate solution. The two phase system was stirred for30 minutes at room temperature. The organic layer was separated, driedover sodium sulfate and evaporated. Crystallization of the residue frommethylene chloride/ether yielded product with m.p. 182°-188°. Theanalytical sample was recrystallized from ethyl acetate/hexane, m.p.183°-185°.

EXAMPLE 1638-Chloro-N-(2-dimethylaminoethyl)-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

2-(Dimethylamino)ethylamine, 5 ml., was added to a solution of acidchloride prepared as described above from 1.85 g. (5 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-][1,4]benzodiazepine-3-carboxylicacid and 1.25 g. of phosphorus pentachloride in 250 ml. of methylenechloride. Following the addition of 100 ml. of 10% aqueous sodiumcarbonate solution, the mixture was stirred for 30 minutes at roomtemperature. The methylene chloride layer was separated, dried andevaporated. Crystallization of the residue from 2-propanol/ether yieldedproduct with m.p. 209°-211°. The analytical sample was recrystallizedfrom ethyl acetate/hexane, m.p. 210°-213°.

EXAMPLE 1648-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Methanolic ammonia, 20 ml., 25%, was added to a solution of acidchloride prepared as described in the previous example from 1.85 g. of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid and 1.25 g. of phosphorus pentachloride in 250 ml. of methylenechloride. After stirring for 10 minutes, 50 ml. of 10% aqueous sodiumcarbonate solution was added and stirring was continued for 1 hour atroom temperature. The methylene chloride layer was separated, dried andevaporated. The residue was dissolved in a mixture of methylene chlorideand ethanol. The solution was filtered over a bed of silica gel and thefiltrate was evaporated. Crystallization of the residue from ethanolgave the product as colorless crystals. The analytical sample wasrecrystallized from ethanol/tetrahydrofuran, m.p. 300°-305°.

EXAMPLE 1658-Chloro-6-(2-fluorophenyl)-1,N,N-trimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Dimethylamine, 4 ml. was added to a solution of the acid chlorideprepared as in the previous example from 1.85 g. (0.005 m) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, and 1.25 g. (0.006 m) of phosphorus pentachloride in 250 ml. ofmethylene chloride. After stirring at room temperature for 1 hour, thereaction mixture was washed with 10% aqueous sodium carbonate solution,was dried and evaporated. The residue was purified by chromatographyover 40 g. of silica gel using 5% (v/v) of ethanol in methylene cloride.Crystallization of the combined clean fractions from ether/hexaneyielded product as colorless crystals, m.p. 177°-179°. A lower meltingmodification with m.p. 158°-160° was also observed.

EXAMPLE 1661-[8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-3-oyl]pyrrolidine

Pyrrolidine, 4 ml., was added to a solution of acid chloride prepared asdescribed above from 1.85 g. of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid and 1.25 g. of phosphorus pentachloride in 250 ml. of methylenechloride. Subsequently 100 ml. of 10% aqueous sodium carbonate solutionwas added and the two phase mixture was stirred at room temperature for1 hour. The organic phase was separated, dried and evaporated.Crystallization of the residue from 2-propanol/ether gave colorlessproduct with m.p. 220°-221° after recrystallization from ethylacetate/hexane.

EXAMPLE 1678-Chloro-6-(2-fluorophenyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, 2,2-dimethylhydrazide

2,2-Dimethylhydrazine, 10 ml., was added to a solution of acid chlorideprepared as described above from 1.85 g. of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid and 1.25 g. of phosphorus pentachloride in 250 ml. of methylenechloride. After addition of 100 ml. of 10% aqueous sodium carbonatesolution the mixture was stirred for 30 minutes at room temperature. Theorganic layer was separated, dried and evaporated. Crystallization ofthe residue from ether/ethanol yielded colorless product. The analyticalsample was purified by chromatography over 30 fold amount of silica gel,using 10% (v/v) of ethanol in methylene chloride. It was crystallizedfrom methylene chloride/ethyl acetate/hexane, m.p. 238°-240°.

EXAMPLE 168

8-Chloro-6-(2-fluorophenyl)-3-(methyoxycarbonylamino)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 1.85 g. (5 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, 1.5 g. of diphenylphosphoric azide, 30 ml. of dimethylformamideand 2 ml. of triethylamine was stirred at room temperature for 15minutes. 6 Ml. of methanol was added and the reaction mixture was heatedto reflux for 30 minutes. The solvent was removed under reducedpressure, at the end azeotropically with xylene. Crystallization of theresidue from ethyl acetate yielded product which was recrystallized frommethylene chloride/methanol/ethyl acetate, m.p. 270°-275°. Theanalytical sample was recrystallized from tetrahydrofuran/ethanol, m.p.272°-275° dec.

EXAMPLE 1693-(Benzyloxycarbonylamino)-8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 1.85 g. (5 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, 1.5 g. of diphenylphosphoric azide, 10 ml. of dimethylformamide,25 ml. of toluene and 2 ml. of triethylamine was stirred at roomtemperature for 10 minutes. Benzyl alcohol, 10 ml., was added and themixture was heated to reflux for 30 minutes. After evaporation of thesolvents under reduced pressure, the residue was crystallized from etherto yield product with m.p. 250°-253°. The analytical sample wasrecrystallized from methylene chloride/methanol/ethyl acetate, m.p.253°-255°.

EXAMPLE 170

8-Chloro-3-methoxycarbonylamino-1-methyl-5-nitroso-6-phenyl-5,6-dihydro-4H-imidazo[1,5-][1,4]benzodiazepine

Sodium nitrite, 1.8 g. (2.5 mmol), was added in portions over a 5 minuteperiod to a solution of 3.7 g. (10 mmol) of8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid hydrazide in 35 ml. of glacial acetic acid. After stirring for 30minutes at room temperature, the azide was precipitated by addition ofice and water. The solids were collected and dissolved in methylenechloride. The solution was washed with water, sodium bicarbonatesolution and ice, was dried and evaporated. The residue was dissolved ina mixture of 100 ml. of dimethylformamide and 25 ml. of methanol andheated to reflux for 20 minutes (temperature ca 103°). The solvents wereremoved under reduced pressure and the residue was crystallized frommethanol/ethyl acetate to yield colorless crystals with m.p. 255°-258°dec. The analytical sample was recrystallized fromtetrahydrofuran/ethanol and had the same melting point.

EXAMPLE 171 8-Chloro-5,6-dihydro-3-(methoxycarbonylamino)-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

8-Chloro-3-methoxycarbonylamino-1-methyl-5-nitroso-6-phenyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine,2.06 g. (5 mmol) was dissolved by warming in a mixture of 200 ml. oftetrahydrofuran and 100 ml. of methanol. After addition of Raney nickel(2 teaspoonsful) the mixture was hydrogenated at atmospheric pressurefor 1 hour. The catalyst was separated by filtration and the filtratewas evaporated. Crystallization of the residue from methanol yieldedcolorless crystals with m.p. 280°-290° dec. The analytical sample wasrecrystallized from ethyl acetate/methanol.

EXAMPLE 172

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A mixture of 9.75 g. (0.03 m) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,200 ml. of methylene chloride and 12 g. (0.07 m) of m-chloroperbenzoicacid was stirred for 11/2 hours. The solution was then extracted with3×150 ml. of 1 N hydrochloric acid. The extracts were washed with ether,made alkaline with ammonia and extracted with methylene chloride. Themethylene chloride extracts were dried and evaporated and the residuewas crystallized from ethyl acetate to leave product which was furtherpurified by chromatography over 100 g. of silica gel using 5% (v/v) ofethanol in methylene chloride. The clean fractions were combined andevaporated. Crystallization of the residue from ethyl acetate/etheryielded colorless crystals with m.p. 245°-246° dec.

EXAMPLE 1734-Acetoxy-8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 4 g. of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide in 100 ml. of acetic anhydride was heated on the steam bath for24 hours. The reagent was evaporated under reduced pressure, at the endazeotropically with xylene. The residue was chromatographed over 80 g.of silica gel using 20% (v/v) methylene chloride in ethyl acetate.Crystallization of the clean fractions from methylene chloride/etheryielded colorless crystals, m.p. 201°-202°.

EXAMPLE 1748-Chloro-6-(2-fluorophenyl)-4-hydroxy-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

4-Acetoxy-8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,0.5 g. (1.3 mmol) was added to 40 ml. of methanol containing 4 mmol ofsodium methoxide. After stirring under nitrogen for 1/2 hour at roomtemperature, the solvent was evaporated under reduced pressure. Theresidue was dissolved in water and the solution was acidified withacetic acid. The precipitated crystals were collected and dissolved inmethylene chloride. The solution was dried and evaporated and theresidue was crystallized from methylene chloride/ether to yieldcolorless crystals with m.p. 185°-186°.

EXAMPLE 1758-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine2,5-dioxide

A mixture of 9.75 g. (0.03 m) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,18 g. (0.105 m) of m-chloroperbenzoic acid and 200 ml. of methylenechloride was stirred at room temperature overnight. After dilution with500 ml. of ether, the reaction mixture was extracted 4 times with 75 ml.of 1N hydrochloric acid. The extracts were washed with ether, madealkaline with ammonia and extracted with methylene chloride. Theextracts were dried and evaporated. Crystallization from ethyl acetategave8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide.

The aqueous phase was evaporated under reduced pressure to dryness. Theresidue was washed out well with methylene chloride containing 20% ofethanol. The combined washings were evaporated to leave crude2,5-dioxide which was chromatographed over 40 g. of silica gel using 50%of methanol in methylene chloride. After elution of the less polar8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine2-oxide with m.p. 179°-181° dec. after recrystallization from ethylacetate/methanol the pure fractions of the 2,5-dioxide were combined andevaporated. Crystallization from ethyl acetate yielded product asoff-white crystals with m.p. 225°-230° dec. The analytical sample wasrecrystallized from methanol/ethyl acetate.

EXAMPLE 1761-Acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A solution of 1 g. of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine2,5-dioxide in 10 ml. of acetic anhydride was heated on the steambathfor 15 minutes. The reagent was evaporated under reduced pressure andthe residue was crystallized from ethyl acetate/ether to yield crystalswith m.p. 203°-205°. For analysis it was recrystallized from ethylacetate.

EXAMPLE 1771-Acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 1 g. of1-acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide, 30 ml. of methylene chloride and 3 ml. of phosphorustrichloride was allowed to sit at room temperature for 24 hours. Afterevaporation under reduced pressure the residue was partitioned betweenmethylene chloride and saturated sodium bicarbonate solution. Theorganic phase was dried and evaporated. Crystallization of the residuefrom ethyl acetate/hexane gave colorless product with m.p. 151°-152°.For analysis it was recrystallized from ethyl acetate/ether.

EXAMPLE 1788-Chloro-6-(2-fluorophenyl)-1-hydroxymethyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Sodium methoxide, 0.3 g., was added to a solution of 1 g. of1-acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepinein 20 ml. of methanol. After standing for 10 minutes at roomtemperature, the separated crystals were collected, washed with aqueousmethanol, methanol and ether to yield colorless product. The analyticalsample was recrystallized from methylene chloride/ethanol, m.p.258°-260°.

EXAMPLE 1798-Chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzoidazepine-1-carboxaldehyde

A mixture of 0.2 g. of8-chloro-6-(2-fluorophenyl)-1-hydroxymethyl-4H-imidazo[1,5-a][1,4]benzodiazepine,20 ml. of methylene chloride and 1 g. of activated manganese dioxide wasstirred at room temperature for 2 hours. The manganese dioxide wasremoved by filtration over celite and the filtrate was evaporated.Crystallization of the residue from methylene chloride/ethylacetate/hexane gave product as colorless crystals with m.p. 182°-183°.

EXAMPLE 1803-Bromo-8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

N-bromosuccinimide, 13.7 g (0.077 m) was added to a stirred solution of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,10 g. (0.030 m) in 450 ml. of chloroform and 30 ml. of glacial aceticacid. The mixture was stirred under reflux for 1.5 hours and thencooled. The mixture was then washed with saturated sodium bicarbonatesolution and the chloroform layer dried and evaporated. The oily residuewas chromatographed using 150 g. of Woelm neutral aluminum oxide.Impurities were removed first with methylene chloride, followed by ethylacetate to remove the product. The fractions containing product werecombined and evaporated. Crystallization of the residue with etheryielded product with m.p. 201°-205° C. The analytical sample wasrecrystallized from ether/hexane, m.p. 203°-205° C.

EXAMPLE 1818-Chloro-3-cyano-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 2.45 g. (0.07 m) of8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide,50 ml. of pyridine and 7 g. of phosphorus pentoxide was heated to refluxfor 15 minutes. The pyridine was evaporated under reduced pressure andthe residue was partitioned between ice, 10% sodium carbonate solutionand methylene chloride. The organic layer was separated, dried andevaporated. The residue was chromatographed over 50 g. of silica gelusing ethyl acetate/methylene chloride 1:1. Crystallization from ethylacetate/hexane yielded product with m.p. 228°-229°.

EXAMPLE 1828-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde

Activated manganese dioxide, 5 g., was added to a solution of 1 g. of8-chloro-6-(2-chlorophenyl)-3-hydroxymethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 50 ml. of methylene chloride. The mixture was stirred at roomtemperature for 2 hours. The manganese dioxide was filtered off and thefiltrate was evaporated. Crystallization of the residue from ethanolgave product as colorless crystals with m.p. 237°-239°. The analyticalsample was recrystallized from tetrahydrofuran/ethanol.

EXAMPLE 1838-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldoxime

A mixture of 1.4 g. (4 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde,2 ml. of triethylamine, 30 ml. of ethanol and 0.56 g. (8 mmol) ofhydroxylamine hydrochloride was allowed to stand at room temperature for11/2 hours. After dilution with water the precipitated crystals werecollected and dried to yield oxime with m.p. 269°-271°. The analyticalsample was recrystallized from tetrahydrofuran/ethanol, m.p. 272--275°.

EXAMPLE 1842-[(Amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine

7-Chloro-5-(2-chlorophenyl)-alpha-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid, methyl ester, 7.8 g. (0.02 m) was dissolved in a mixture of 200ml. of tetrahydrofuran and 100 ml. of ethanol by warming. The solutionwas hydrogenated in the presence of Raney nickel (2 teaspoonsful) atatmospheric pressure for 2 hours. The catalyst was separated byfiltration over Celite and the filtrate was evaporated under reducedpressure. Crystallization of the residue from ethanol gave product asorange crystals with m.p. 115°-117° dec. Recrystallization of thissolvated product from ether/hexane gave yellow needles with m.p.145°-150° dec.

EXAMPLE 185 Methyl 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Acetaldehyde, 0.25 ml., was added to a solution of 0.5 g. of 2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepinein 25 ml. of methylene chloride. Following the addition of molecularsieves 5A, the mixture was stirred at room temperature for 15 minutes.Activated manganese dioxide, 1g., was then added and stirring wascontinued for 30 minutes. The solid material was separated by filtrationover celite and the filtrate ;was evaporated. Crystallization of theresidue from ethyl acetate/hexane gave product with m.p. 228°-230°.

EXAMPLE 1868-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid

A stirred solution of 4.1 g. (0.01 m) of ethyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 100 ml. of methanol containing 3 ml. of water and 1.2 g. (0.02 m) ofpotassium hydroxide was heated at reflux under nitrogen for 4.5 hoursand concentrated at reduced pressure to remove the methanol. The residuewas dissolved in cold water and acidified with acetic acid to give anoff-white solid. After air drying on the funnel overnight, product wasobtained. Recrystallization of a sample from 1:1 methylenechloride/ethanol gave white platelets, m.p. 265°-267° (dec.).

EXAMPLE 1878-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A stirred suspension of 1.2 g. (0.0031 m) of ethyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 25 ml. of methylene chloride was cooled in an ice bath and tretaedwith 0.7 g. (0.004 m) of phosphorus pentachloride in portions. Themixture was protected by a drying tube and stirring in the cold wascontinued 30 minutes longer during which time most of the soliddissolved. With continued cooling and stirring, the mixture was treatedwith gaseous ammonia for 5 minutes and stirred an additional 30 minutesin the cold. The mixture was evaporated in vacuo to give a light solidwhich was stirred with dilute aqueous ammonia and filtered through acoarse sintered glass funnel. After washing with water the solid was airdried on the funnel to give product. Recrystallization of a sample from2:1 methylene chloride/ethanol solution gave white plates, m.p.318°-320° (dec.).

EXAMPLE 1885-Aminomethyl-1-[4-chloro-2-(2-fluorobenxzoyl)phenyl]-2-methylimidazoledihydrochloride

A solution of 25 g. of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 50 ml. of water and 50 ml. of concentrated hydrochloric acid wasallowed to stand at room temperature for 3 hours. Following addition of250 ml. of 2-propanol the mixture was evaporated partially under reducedpressure without heating. Additional 200 ml. of 2-propanol were addedand partial evaporation was resumed. The precipitated crystals werecollected and washed well with 2-propanol and ether to yield productwith m.p. 302°-307° (dec.). The analytical sample was recrystallizedfrom methanol/2-propanol without heating.

EXAMPLE 1893-Acetamino-8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.2 g. of3-(benzyloxycarbonylamino)-8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 10 ml. of glacial acetic acid and 2 ml. of acetic anhydride washydrogenated over palladium on charcoal (10%) for 1 hour at atmosphericpressure. The catalyst was filtered off and the filtrate was evaporated,at the end azeotropically with xylene. The residue was chromatographedover 6 g. of silica gel using 10% ethanol in methylene chloride.Crystallization of the combined pure fractions from ethyl acetate/ethergave product as colorless crystals with m.p. 175°-178°.

EXAMPLE 190 Methyl8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-4-carboxylate

Potassium t-butoxide, 0.25 g. (2.2 mmol) was added to a solution of 0.65g. (2 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 10 ml. of dimethylformamide cooled to -30°. After stirring undernitrogen for 10 minutes, 0.2 ml. of methyl chloroformate was added inone portion at -30°. When the reaction mixture had warmed to 0° it waspartitioned between methylene chloride and saturated sodium bicarbonatesolution. The methylene chloride layer was diluted with benzene andwashed with bicarbonate solution and water, was dried and evaporated.The residue was chromatographed over 20 g. of silica gel using ethylacetate. Crystallization of the combined clean fractions of product fromether yielded colorless crystals with m.p. 203°-205°. The analyticalsample was recrystallized from ethyl acetate/hexane.

EXAMPLE 1918-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldoxime

Hydroxylamine hydrochloride, 0.14 g. (2 mmol) was added to a suspensionof 0.37 g. (1 mmol) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehydein 10 ml. of ethanol and 0.5 ml. of triethylamine. The mixture washeated on the steambath until solution was complete and the solution wasallowed to stand for 2 hours. The separated crystals were collected,washed with water, ethanol and ether to yield oxime. The analyticalsample was recrystallized from tetrahydrofuran/ethanol, m.p. 290°-292°dec.

EXAMPLE 1928-Chloro-6-(2-chlorophenyl)-3-(1-hydroxyethyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of methyl magnesium iodide in ether, 5 ml., ca. 1-molar, wasadded to a solution of 0.37 g. (1 mmol) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehydein 10 ml. of tetrahydrofuran. After sitting for 15 minutes at roomtemperature the mixture was decomposed with water. The inorganicmaterial was filtered off and washed with methylene chloride. Thefiltrate was dried and evaporated. Crystallization of the residue fromether and recrystallization from ethyl acetate/hexane gave product ascolorless crystals with m.p. 197°-199°.

EXAMPLE 1933-Acetyl-8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.1 g. of8-chloro-6-(2-chlorophenyl)-3-(1-hydroxyethyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 20 ml. of methylene chloride was stirred at room temperature for 3hours in the presence of 0.5 g. of activated manganese dioxide. Themanganese dioxide was filtered off and the filtrate was evaporated. Thecrystalline residue was recrystallized from ethyl acetate/hexane toyield product as colorless crystals with m.p. 234°-236°.

EXAMPLE 194 2-Methylamino-5-phenyl-3H-thieno-[3,2-e][1,4]diazepine

A mixture of 10 g. (0.036 m) of1,3-dihydro-5-phenyl-2H-thieno-[3,2-e][1,4]diazepine-2-one in 50 ml. ofbenzene and 300 ml. of tetrahydrofuran was stirred on an ice bath andsaturated with methylamine gas. To this mixture was added dropwise asolution of titanium tetrachloride, 9.48 g. (0.05 m) in 50 ml. ofbenzene. After the addition was complete, the mixture was stirred on theice bath for 15 minutes. The ice bath was then replaced with a heatingmantel and the mixture refluxed for 1/2 hour. The mixture was cooled and100 g. of ice carefully added. The mixture was filtered and the residuewashed with tetrahydrofuran. The filtrates were combined, dried andevaporated. The product was crystallised from methylene chloride toyield product, m.p. 223°-227°. From the concentrated mother liquors wasobtained additional product, m.p. 222°-225°. The analytical sample wasrecrystallized from methylene chloride, m.p. 227°-229°.

EXAMPLE 1957-Chloro-5-phenyl-2-methylamino-3H-thieno-[2,3-e][1,4]diazepine

A mixture of 7.7 g. (0.0278 m)7-chloro-1,3-dihydro-5-phenyl-2H-thieno[2,3-e][1,4]diazepin-2-one, 50ml. of benzene and 250 ml. of tetrahydrofuran was stirred on an ice bathand saturated with methylamine gas. To this mixture was added a solutionof titanium tetrachloride (7.38 g.), (0.0389 m) in 50 ml. of benzenefrom a dropping funnel. After the addition was complete, the mixture wasstirred on the ice bath for 15 minutes. The ice bath was then replacedby a heating mantel and the reaction mixture was refluxed for 20minutes. The mixture was cooled and 100 g. of ice were carefully added.The mixture was then filtered, and the residue washed withtetrahydrofuran. The filtrates were combined, dried and evaporated. Theproduct was crystallised from methylene chloride/ether m.p. 246°-249°.The analytical sample was recrystallized from methylene chloride, m.p.247°-250°.

EXAMPLE 196 7-Chloro-5-(2-chlorophenyl)-2-methylamino-3H-thieno[2,3-e][1,4]diazepine

A solution of 50 g. (0.161 m) of7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one,in 900 ml. of dry tetrahydrofuran and 300 ml. of dry benzene was cooledin an ice bath, and methylamine was bubbled in until the solution wassaturated, a solution of 40 g. (0.209 m) of titanium tetrachloride in100 ml. of benzene was added dropwise with stirring. After 4 hours atroom temperature a few grams of ice were added and the reaction wasfiltered. The precipitate was washed several times with hottetrahydrofuran, and the combined filtrates were evaporated. The residuewas partitioned between 250 ml. of dichloromethane and 200 ml. of waterand filtered. The dichloromethane solution was separated, dried andevaporated. This residue and the precipitate were recrystallized from amixture of tetrahydrofuran and ethanol to give product. A sample wasrecrystallized for analysis from a mixture of tetrahydrofuran and hexaneto give pale yellow prisms, m.p. 259°-262°.

EXAMPLE 1972-(N-nitrosomethylamino)-5-phenyl-3H-thieno[3,2-e][1,4]diazepine

Nitrosyl chloride was introduced into a solution of 7.8 g. (0.03 m) of2-methylamino-5-phenyl-3H-thieno[3,2-e][1,4]diazepine in 100 ml. ofmethylene chloride and 40 ml. of pyridine cooled in ice water. Thereaction was monitored by thin layer chromatography and when thestarting material had disappeared the nitrosyl chloride addition wasterminated and the reaction mixture was partitioned between methylenechloride and water. The methylene chloride solution was dried andevaporated. Crystallization of the residue from methylenechloride/hexane yielded product as yellow crystals with m.p. 156°-159°.The analytical sample was recrystallized from ether/hexane, m.p.158°-160°.

EXAMPLE 1987-Chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-thieno[2,3-e][1,4]diazepine

Nitrosyl chloride was introduced into a solution of 5.8 g. (0.02 m) of7-chloro-5-phenyl-2-methylamino-3H-thieno[2,3-e][1,4]diazepine in 100ml. of methylene chloride and 50 ml. of pyridine until the reaction wascomplete according to thin layer chromatogram. The mixture waspartitioned between water and toluene. The organic phase was dried andevaporated. Crystallization of the residue from ether/hexane yieldedproduct as yellow crystals with m.p. 108°-110°. For analysis it wasrecrystallized from ether/hexane, m.p. 111°-113°.

EXAMPLE 1997-Chloro-5-(2-chlorophenyl)-2-(N-nitrosomethylamino)-3H-thieno]2,3-e][1,4]diazepine

A mixture of 40 g. (0.123 m) of7-chloro-5-(2-chlorophenyl)-2-(N-nitrosomethylamino)-3H-thieno[2,3-e][1,4]diazepine,700 ml. of dichloromethane an d 350 ml. of pyridine was cooled in an icebath and nitrosyl chloride was bubbled in for 20 minutes with stirring.After 1 hour it was bubbled in for 5 minutes more and then 600 ml. ofwater was added slowly. The dichloromethane layer was separated, washedwith 200 ml. of water, dried over anhydrous sodium sulfate andevaporated to dryness. The oil was dissolved in dichloromethane andfiltered through 400 g. of Florisil. This was eluted withdichloromethane, and then ether. Crystallization of the dichloromethanefraction from a mixture of ether and petroleum ether gave product andmore product was obtained from the ether fraction. A sample wasrecrystallized for analysis from a mixture of ether and petroleum etherto give yellow prisms, m.p. 104°-107°.

EXAMPLE 200 1,2-Dihydro-2-nitromethylene-5-phenyl-3H-thieno[3,2-e][1,4]diazepine

2-(N-nitrosomethylamino)-5-phenyl-3H-thieno[3,2-e][1,4]diazepine, 5.7 g.(0.02 m) was added to a mixture of 15 ml. of nitromethane, 4.5 g. ofpotassium t-butoxide and 60 ml. of dimethylformamide which had beenstirred for 10 minutes at room temperature. Following addition, thereaction mixture was stirred under nitrogen and heated on the steam bathfor 10 minutes. After acidification with 4 ml. of glacial acetic acidthe mixture was partitioned between methylene chloride/toluene andsaturated sodium bicarbonate solution. The organic layer was washed withwater, dried and evaporated. Crystallization of the residue frommethanol with seeding yielded product as yellow crystals, m.p.160°-163°. Seeds were obtained by chromatographic purification over 30fold amount of silica gel using 10% (v/v) of ethyl acetate in methylenechloride. The analytical sample was recrystallized from methanol, m.p.163°-164°.

EXAMPLE 2017-Chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno[2,3-e][1,4]diazepine

7-Chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-thieno[2,3-e][1,4]diazepine,3.2 g. (0.01 m), was added to a mixture of 10 ml. of nitromethane, 35ml. of dimethylformamide and 2.26 g. (0.02 m) of potassium t-butoxidewhich had been stirred under nitrogen for 10 minutes at roomtemperature. After heating for 10 minutes on the steam bath the reactionmixture was acidified by addition of 2 ml. of glacial acetic acid andwas partitioned between water and toluene. The toluene layer was washedwith water, dried and evaporated. The residue crystallized from ethylacetate/hexane to yield crude product. It was purified by chromatographyover 40 g. of silica gel using 10% (v/v) of ethyl acetate in methylenechloride. The pure product was obtained as yellow crystals with m.p.154°-156° C.

EXAMPLE 2022-Aminomethyl-2,3-dihydro-5-phenyl-1H-thieno[3,2-e][1,4]diazepinedimaleate

A solution of 1.42 g. (5 mmol) of1,2-dihydro-2-nitromethylene-5-phenyl-3H-thieno[3,2-e][1,4]diazepine in200 ml. of ethanol was hydrogenated over Raney nickel (2 teaspoonful)for 1 hour at atmospheric pressure. The catalyst was removed byfiltration and the filtrate was evaporated. The residue was treated with1.2 g. of maleic acid in 10 ml. of 2-propanol. The salt was crystallizedby addition of ether to yield product as yellow crystals with m.p.170°-173°. The analytical sample was recrystallized frommethanol/2-propanol, m.p. 187°-189°.

EXAMPLE 2032-Aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno[2,3-e][1,4]diazepinedimaleate

(A) A solution of 320 mg. (1 mmol) of7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno[2,3-e][1,4]diazepinein 20 ml. of ethanol was hydrogenated over Raney nickel for 5 hours ofatmospheric pressure. The catalyst was removed by filtration and thefiltrate was evaporated. The residue was chromatographed over 7 g. ofsilica gel using methylene chloride, methanol, triethylamine in a ratioof 13:6:1. The fractions containing pure product were combined,evaporated and the residue was treated with maleic acid in 2-propanol.Crystallization of the dimaleate salt from 2-propanol/ether andrecrystallization from ethyl acetate/ethanol yielded yellow crystals,m.p. 176°-177° C.

(B) A solution of 320 mg. (1 mmol) of7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno[2,3-e][1,4]diazepinein 3 ml. of tetrahydrofuran was added to a suspension of 0.8 g. oflithium aluminum hydride in 20 ml. of tetrahydrofuran. After heating toreflux for 5 minutes, the reaction mixture was cooled and hydrolyzed byaddition of 5 ml. of water. The inorganic material was separated byfiltration and the filtrate was evaporated. The residue waschromatographed as described above the pure product was converted to themaleate to give dimaleate with m.p. 176°-178°.

EXAMPLE 204 1-Methyl-6phenyl-4H-imidazo[1,5-a]thieno[2,3-f]diazepine

2-Aminomethyl-2,3-dihydro-5-phenyl-1H-thieno[3,2-e][1,4]diazepinedimaleate, 1 g. (2 mmol), was partitioned between methylene chloride andaqueous ammonia. The methylene chloride layer was dried and evaporated.The residue was heated to reflux for 1 hour with 1 ml. of triethylorthoacetate in 20 ml. of xylene. The solvent was evaporated underreduced pressure and the residue was crystallized from 2propanol/etherto yield1-methyl-3a,4-dihydro-6-phenyl-3H-imidazo[1,5-a]thieno[2,3-f]diazepinewith m.p. 150°-152°. This material was heated to reflux in 30 ml. oftoluene with 2 g. of activated manganese dioxide for 2 hours. Themanganese dioxide was filtered off and washed well with methylenechloride. The filtrate was evaporated and the residue waschromatographed over 7 g. of silica gel using 3% (v/v) of ethanol inmethylene chloride. The fractions containing pure product were combinedand evaporated. Crystallization from methylene chloride/ether andrecrystallization from ethyl acetate/hexane yielded product with m.p.223°-225°.

EXAMPLE 2058-Chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine

2-Aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno[2,3-e][1,4]diazepinedimaleate, 0.52 g. (1 mmol) was partitioned between methylene chlorideand aqueous ammonia. The methylene chloride solution was dried andevaporated. The residue was heated to reflux for 1 hour with 0.5 ml. oftriethyl orthoacetate in 10 ml. of xylene. The crude product obtainedafter evaporation under reduced pressure was dissolved in 25 ml. oftoluene and the solution was heated to reflux for 11/2 hours afteraddition of 2.5 g. of activated manganese dioxide. The manganese dioxidewas then filtered off and the filtrate was evaporated. The residue waschromatographed over 6 g. of silica gel using 4% (v/v) of ethanol inmethylene chloride. Fractions containing the pure compound were combinedand evaporated. Crystallization of the residue from ether/hexane yieldedproduct with m.p. 168°-170° C.

EXAMPLE 2067-Chloro-5-(2-chlorophenyl)-1,3-dihydro-2-dimethoxymalonylidene-2H-thieno[2,3-e][1,4]diazepine

A mixture of 3.4 g. (0.03 m) of potassium t-butoxide, 7 ml. ofdimethylmalonate and 20 ml. of dimethylformamide was stirred for 5minutes under an atmosphere of nitrogen. Following the addition of 3.55g. (0.01 m) of7-chloro-5-(2-chlorophenyl)-2-(N-nitrosomethylamino)-3H-thieno[2,3-e][1,4]diazepine,the mixture was stirred and heated on the steambath for 5 minutes, wasacidified by addition of 3 ml. of acetic acid an crystallized by slowaddition of water. The precipitated material was collected, washed withwater and methanol and dissolved in methylene chloride. The solution wasdried and evaporated and the residue was crystallized from ethanol toyield pinkish crystals which were recrystallized from ethanol foranalysis, m.p. 158°-160°.

EXAMPLE 2077-Chloro-5-(2-chlorophenyl)-alpha-hydroxyimino-3H-thieno[2,3-e][1,4]diazepine-2-aceticacid, methyl ester

A mixture of 2.15 g. (5 mmol) of7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2-dimethyoxymalonylidene-2H-thieno[2,3-e][1,4]diazepine,50 ml. of methanol and 0.7 g. (1.25 mmol) of potassium hydroxide washeated to reflux under nitrogen for 3 hours. The solvent was partiallyevaporated and the residue was partitioned between methylene chlorideand saturated sodium bicarbonate solution. The organic phase was driedand evaporated. The crude7-chloro-5-)2-clorophenyl)-2,3-dihydro-2-(methoxycarbonylmethylene)-2H-thieno[2,3-e][1,4]diazepineobtained was dissolved in 20 ml. of glacial acetic acid. Sodium nitrite,0.5 g., was added and the mixture was stirred for 15 minutes at roomtemperature, diluted with water and extracted with methylene chloride.The extracts were washed with water and sodium bicarbonate solution,dried and evaporated. Crystallization of the residue from methylenechloride/ether and recrystallization from tetrahydrofuran/methanol gaveyellow crystals with m.p. 242°-245° dec.

EXAMPLE 208 Methyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-3-carboxylate

7-Chloro-5-(2-chlorophenyl)-alpha-hydroxyimino-3H-thien[3,2-f][1,4]diazepine-2-aceticacid, methyl ester, 0.4 g. (1 mmol) was dissolved by warming in 30 ml.of tetrahydrofuran and 20 ml. of ethanol. Following the addition ofRaney nickel (1/2 teaspoonful) the mixture was hydrogenated for 45minutes at atmospheric pressure. The catalyst was filtered off and thefiltrate was evaporated. The residue was dissolved in 10 ml. of methanoland treated with 0.4 ml. of triethyl orthoacetate and 3 drops ofethanolic hydrogen chloride. After heating to reflux for 10 minutes thesolvent was evaporated and the residue was partitioned between methylenechloride and sodium bicarbonate solution. The organic layer was driedand evaporated. Chromatography of the residue over 10 g. of silica gelusing methylene chloride/ethyl acetate 3:5 (v/v) and crystallization ofthe residue obtained after removal of the eluent from ethanol yieldedproduct with m.p. 211°-212°.

EXAMPLE 209 8-Chloro-6-(2-chlorophenyl)-3-hydroxymethyl-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine

To 20 ml. of ether under nitrogen was added 38 mg. (0.001 m) of lithiumaluminum hydride. The reaction was cooled in an ice bath and 0.2 g.(0.000493 m) of methyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-3-carboxylatewas dissolved in 20 ml. of dry tetrahydrofuran and added dropwise withstirring to the reaction. After one hour 5 ml. of ethyl acetate wasadded followed by 3 ml. of a saturated solution of sodium bicarbonate.The reaction was filtered through Celite, which was then washed withdichloromethane and the combined filtrates were evaporated andcrystallized from a mixture of dichloromethane and ether.Recrystallization from the same solvents gave off-white prisms, m.p.100°-110° resets, m.p. 190°-194° C.

EXAMPLE 2108-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-3-carboxylicacid

To 10 ml. of methanol and 1 ml. of water was added 0.1 g. (0.000247 m)of methyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-3-carboxylateand 0.028 g. (0.000493 m) of potassium hydroxide. The reaction wasrefluxed for 2 hours and evaporated. The residue was dissolved in 10 ml.of water, washed with 10 ml. of ether and then acidified with aceticacid. This was extracted with 30 ml. of dichloromethane, which was driedover anhydrous sodium sulfate, concentrated, cooled and filtered.Recrystallization of the precipitate from a mixture of dichlormethaneand ether gave white prisms, m.p. 242°-247°.

EXAMPLE 2118-Chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-3-carboxamide

To 0.8 g. (0.00204 m) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-3-carboxylicacid in 100 ml. of dry dichloromethane in an ice bath was added 0.46 g.(0.0022 m) of phosphorus pentachloride. After 30 minutes ammonia wasbubbled in for 5 minutes with stirring. After 2 hours 75 ml. of waterwas added and the product was filered off. The dichloromethane wasseparated, dried and evaporated. The product obtained by crystallizationof the residue from ethanol was combined with the first precipitate andrecrystallized from a mixture of chloroform and ethanol to give whiterods, m.p. 300°-305°.

EXAMPLE 212 Methyl8-Chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A solution of 1.15 g. (2.5 mmol) of2[(benzoylamino)methoxy-carbonylmethylene]-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepinein 10 ml. of hexamethyl phosphoric triamide was heated to reflux for 10minutes. The dark mixture was partitioned between water andether/methylene chloride. The organic layer was washed with water, driedand evaporated. The residue was dissolved in methylene chloride andfiltered over activated aluminum oxide with ethyl acetate. The filtratewas evaporated and chromatographed over 20 g. of silica gel using 10%(v/v) ethyl acetate in methylene chloride. Crystallization of thecombined clean fractions from ether/hexane gave final product with mp208°-209° C.

EXAMPLE 213 Methyl8-chloro-6-(2-chlorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A mixture of 375 mg. of2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine,20 ml. of toluene and 0.5 ml. of benzaldehyde was heated to reflux for10 minutes over molecular sieves 5A. Following the addition of 1 g. ofactivated manganese dioxide refluxing was continued for another 10minutes. The mixture was filtered over Celite and the filtrate wasevaporated. The crystalline residue was collected with ether andrecrystallized from ethyl acetate/hexane to yield off-white crystalswith m.p. 272°-275° C.

EXAMPLE 214 Ethyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate-4-oxide

A stirred solution of 12.4 g. (0.03 m) of ethyl8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 200 ml. of methylene chloride was treated with 12 g. (0.07 m) ofm-chloroperoxybenzoic acid in portions at room temperature. Stirring wascontinued for 2.5 hours. The solution was washed with 1 N sodiumhydroxide solution and the turbid methylene chloride layer wasseparated, diluted with methanol and dried over sodium sulfate.Filtration and evaporation at reduced pressure gave a gum which gaveoff-white crystals when triturated with ether. An analytical sample wasobtained after two recrystallizations from 1:1 ethanol-methylenechloride solution, m.p. 247°-249° C.

EXAMPLE 215 2-Methylamino-5-phenyl-3H-1,4-benzodiazepine

A solution of 23.6 g. (0.10 mole) of1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 1 liter oftetrahydrofuran (containing about 20 moles of monomethylamine) waschilled in an ice bath. To this mixture was added 14 ml. (d=1.73, 0.125mole) of titanium tetrachloride in 200 ml. of benzene.

This mixture was stirred at room temperature for two days. The titaniumcomplex was destroyed with 20 ml. of water. The inorganic salts thatprecipitated, were removed by filtration. The solvent was evaporated invacuo, the residue was partitioned between methylene chloride and water.A colorless amorphous solid m.p. 227°-229° C. was removed by filtration.An additional sample, m.p. 226°-228° C. of a colorless solid wasobtained from the methylene chloride mother liquors after drying overanhydrous sodium sulfate, evaporation to dryness, and crystallizationfrom ethyl acetate.

An analytical sample was prepared by recrystallization fromdimethylformamide to yield colorless prisms, m.p. 227°-229° C.

EXAMPLE 2167-Ethyl-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine

A solution of 56.4 g. (0.20 mole) of1,3-dihydro-7-ethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 2.0l. of tetrahydrofuran containing 4 moles of monomethylamine was chilledin an ice bath. To this was added 33.0 ml. (0.30 mole) of titaniumtetrachloride in 350 ml. of benzene. The mixture was stirred at roomtemperature for three days.

The titanium tetrachloride was decomposed with 100 ml. of water. Theinorganic salts were removed by filtration. The filtrate was evaporatedto dryness in vacuo. The residue was partitioned between methylenechloride and water. The methylene chloride layer was dried overanhydrous sodium sulfate, evaporated to dryness in vacuo. The residue oncrystallization from acetonitrile yielded the amidine as light yellowprisms, m.p. 172°-174° C.

An analytical sample was prepared by recrystallization from acetonitrileto give light yellow prisms, m.p. 172°-174° C.

EXAMPLE 2178-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid

To a solution of 2.66 g (5.77 mmol) of methyl8-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 50 ml of refluxing methanol was added a solution of 755 mg (11.5mmol) of potassium hydroxide in 10 ml of water and the resulting mixturewas heated for 2.5 hr. The solvent was removed in vacuo, the residue wasdissolved in 50 ml of hot acetic acid and the solution was then pouredinto 100 ml of cold water. The product was collected, washed with waterand air dried to give the title compound as an off-white solid. Ananalytical sample was recrystallized from benzene, mp 267°-269°.

EXAMPLE 2188-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A suspension of 1.5 g (3.48 mmol) of8-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 20 ml of mineral oil was stirred vigorously at 190° for 1/2 hr.The dark suspension was then slurried with hexane and extracted twicewith 1 N hydrochloric acid. The acidic aqueous layer was then washedonce with hexane and neutralized with 5% aqueous sodium carbonate. Theprecipitated product was collected and air dried; concentration of thefiltrate gave an additional yield of the title compound as an off-whitesolid. An analytical sample was obtained by column chromatography onsilica gel eluting with ethyl acetate, mp 241°-243°.

EXAMPLE 219N,N-Dimethyl-[8-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine]-3-carboxamide

A solution of 1.0 g (2.31 mmol) of8-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 5 ml of thionyl chloride was refluxed for 1/2 hr., thencautiously added dropwise to 70 ml of cold 40% aqueous dimethylamine.The brown solid was collected, washed with water, dried andchromatographed on silica gel using ethyl acetate as the eluent to givethe title compound as a brown foam. Recrystallization three times fromacetone-water gave the analytical sample, mp 221°-223°.

EXAMPLE 2208-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A solution of 1.0 g (2.31 mmol) of8-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 5 ml of thionyl chloride was refluxed for 1/2 hr., thencautiously added dropwise to 70 ml of cold ammonium hydroxide. The pinksolid was collected, washed with water, air dried and chromatographed onsilica gel using ethyl acetate as the eluent to give the title compoundas a brown foam. Trituration with acetone gave the analytical sample asa white powder, mp 260°-262°.

EXAMPLE 2212-chloro-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H,11H-imidazo[1,5-a]oxazolo-[3,2-d][1,4]benzodiazepine

A solution of 0.7 g (0.00203 m) of(2-fluorophenyl)-[2-[5-hydroxymethyl-2-methyl-1-imidazolyl)-5-chlorophenyl]methanonein 40 ml of dry dichloromethane was cooled in an ice bath and 0.22 ml(0.00227 m) of phosphorus tribromide was added with stirring. After 1hr. at room temperature the mixture was cooled in an ice bath and 2 ml(0.0328 m) of ethanolamine was added. The solution was stirred for 2hrs. at room temperature, refluxed for 1 hr. and then poured into 50 mlof water. The organic layer was separated, dried over anhydrous sodiumsulfate, and concentrated to a small volume. The residue was developedon 4 silica gel thick layer plates in a solution of 5% methanol in ethylacetate (v/v). The material corresponding to an Rf of 0.5 was removedfrom the plate and treated with methanol. The solution was filtered andthe filtrates were evaporated. The product was crystallized from ether.Recrystallization from a mixture of methanol and ether gave 0.1 g of thepure product as white prisms mp and mmp with an authentic sample176°-181°.

EXAMPLE 222 Methyl1-benzyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Phenylacetaldehyde, 2.4 g (0.02 m), was added to a solution of 3.8 g(0.01 m) of 2-[(amino)methoxycarbonylmethylene]-7-chloro-methylenechloride. Following the addition of 10 g of molecular sieves 5A themixture was stirred at room temperature for 15 min and treated with 10 gof activated maganese dioxide for additional 15 min at room temperature.The inorganic material was separated by filtration over Celite. Thefiltrate was evaporated and the residue was crystallized fromether/hexane to yield colorless crystals with mp 155°-158°. Theanalytical sample was recrystallized from ethyl acetate/hexane, mp160°-162°.

EXAMPLE 2231-Benzyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 2 g (4.2 mmol) of methyl1-benzyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,1 g of potassium hydroxide, 50 ml of methanol and 5 ml of water washeated to reflux for 4 hrs. under an atmosphere of nitrogen. The solventwas evaporated, the residue was dissolved in water and the solution wasacidified with acetic acid. The precipitated crystals were collected,washed with water and dissolved in methylene chloride. The solution wasdried and evaporated. Crystallization from methylene chloride/ethylacetate yielded1-benzyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid with mp 305°-310° dec.

This material was suspended in 30 ml of methylene chloride. Phosphoruspentachloride, 0.8 g was added and the mixture was stirred overice/water for 30 min. Ammonia gas was then introduced until the reactionmixture was alkaline. After stirring for 15 min at room temperature,aqueous ammonia was added and the two phase system was stirred foranother 15 min. The methylene chloride phase was separated, dried andevaporated. The crystalline residue was recrystallized from ethylacetate/methanol to yield colorless product with mp 282°-284°.

The analytical sample was chromatographed over silica gel (40 foldamount) using methylene chloride/ethyl acetate 1:1 (v/v) for elution, mp286°-288°.

EXAMPLE 224 Preparation of3-Ethyl-1,6-dihydro-1-methyl-7-methylamino-4-phenylpyrazolo[3,4-e][1,4]diazepine

A solution of 6.8 g (0.0255 M) of6,8-dihydro-3-ethyl-1-methyl-5-phenylpyrazolo[3,4-e][1,4]diazepin-7(1H)-onein 125 ml of dry tetrahydrofuran and 50 ml of dry benzene was cooled inan ice bath and methylamine was bubbled in until the solution wassaturated. A solution of 6.3 g (0.0331 M) of titanium tetrachloride in20 ml of benzene was then added dropwise with stirring and after 18 hrat room temperature the mixture was refluxed for 30 minutes. Thesolution was cooled, and treated with 4 g of ice. The reaction mixturewas filtered and the precipitate was wasehd with tetrahydrofuran andthen with dichloromethane. The combined filtrates were evaporated todryness and the residue was crystallized from a mixture of methanol andether, and recrystallized from a mixture of dichloromethane and ether togive the product as off-white prisms, mp 218°-221°.

EXAMPLE 225 Preparation of(3-Ethyl-1,6,7,8-tetrahydro-1-methyl-4-phenylpyrazolo[3,4-e][1,4]diazepin-7-ylidene)propanedioic acid, dimethyl ester

A solution of 5.6 g (0.0199 M) of3-ethyl-1,6-dihydro-1-methyl-7-methylamino-4-phenylpyrazolo[3,4-e][1,4]diazepinein 100 ml of dichloromethane and 50 ml of pyridine was stirred in an icebath and nitrosyl chloride was bubbled in for 10 min. After 2 hr at roomtemperature, nitrosyl chloride was bubbled in for an additional 5 min.The mixture was allowed to stand for 30 min when it was poured into 200ml of ice water. The organic layer was separated, washed with 100 ml ofwater, dried over anhydrous sodium sulfate, and filtered through 100 gof Florisil. The Florisil was thoroughly washed with ether, and thecombined filtrates were evaporated to dryness. The intermediateN-nitroso derivative was not further purified but was used in the nextstep as follows.

A mixture of 14 ml of dimethyl malonate and 35 ml ofN,N-dimethylformamide was treated with 6.5 g (0.0580 M) of potassiumtertiary butoxide and after stirring for 5 min a solution of theN-nitroso compound prepared as described above in 10 ml ofN,N-dimethylformamide was added. The resulting mixture was heated on thesteam bath for 5 min, cooled, and 6 ml of glacial acetic acid was added.The reaction mixture was next poured into 300 ml of cold water, andafter 15 min the solution was decanted. The remaining oil was dissolvedin 75 ml of dichloromethane which was washed with 50 ml of diluteammonium hydroxide, dried over anhydrous sodium sulfate andchromatographed through Florisil. The column was eluted first withdichloromethane, then with ether and finally with ethyl acetate. Theether and ethyl acetate fractions were combined and evaporated. Theresidue was crystallized and recrystallized from methanol to give thediester as off-white rods mp 145°-148°.

EXAMPLE 226 Preparation of 3-Ethyl-1,6-dihydro-α-hydroxyimino-1-methyl-4-phenylpyrazolo[3,4-e][1,4]diazepin-7-aceticacid, methyl ester

A solution of 1.7 (0.00445 M) of(3-ethyl-1,6,7,8-tetrahydro-1-methyl-4-phenylpyrazolo[3,4-e][1,4]diazepin-7-ylidene)propanedioic acid, dimethyl ester in 40 ml of methanol was treated withn 0.56 g (0.01 M) of potassium hydroxide, and the solution was refluxedfor 2.5 hr. The solvent was evaporated, and the residue was partitionedbetween 50 ml of dichloromethane and 30 ml of water. The water layer wasfirst acidified with hydrochloric acid then made basic with ammoniumhydroxide and extracted with 75 ml of dichloromethane. The organiclayers were combined, dried over anhydrous sodium sulfate and filteredthrough Florisil. The Florisil was eluted with ether, and then withether acetate. The eluents were combined and evaporated to give thecrude monoester as an oil. This product was not further purified but wasdissolved in 10 ml of glacial acetic acid and treated with 0.35 g (0.005M) of sodium nitrite while stirring. After 45 min the reaction mixturewas poured into 100 ml of water, which was extracted with 75 ml ofdichloromethane. The organic layer was washed with 50 ml of dilutesodium bicarbonate solution, dried over anhydrous sodium sulfate andevaporated to dryness. The product was crystallized from a mixture ofethyl acetate and ether. Recrystallization from a mixture ofdichloromethane and ether gave the pure material as off-white rods, mp225°-227°.

EXAMPLE 227 Method A: Preparation of7-Ethyl-1,9-dimethyl-6-phenyl-4H-9H-imidazo[1,5-a]pyrazolo[4,3-f][1,4]diazepin-3-carboxylicacid, methyl ester

A solution of 0.35 g (0.000986 M) of3-ethyl-1,6-dihydro-α-hydroxyimino-1-methyl-4-phenylpyrazolo[3,4-e][1,4]diazepin-7-aceticacid, methyl ester in 20 ml of dry tetrahydrofuran, and 25 ml ofmethanol was treated with 2 ml (0.0109 M) of triethylorthoacetate and 1spatula of Raney nickel. The reaction mixture was hydrogenated at roomtemperature and atmospheric pressure for 2.5 hr. The catalyst wasremoved by filtration and the spent nickel was washed with methanol. Thecombined filtrates were evaporated and the residue was dissolved in 50ml of dichloromethane. The solution was washed with 40 ml of diluteammonium hydroxide, dried over anhydrous sodium sulfate, and evaporatedto dryness. The residue was refluxed for 20 min in a solution of 50 mlof methanol, containing 2 ml (0.109 M) of triethylorthoacetate and 0.2ml (0.00114 M) of 5.7 N ethanolic hydrogen chloride. Solvents wereremoved by evaporation under reduced pressure and the residue wasdissolved in dichloromethane, which was then washed with dilute ammoniumhydroxide, dried over anhydrous sodium sulfate and evaporated. The crudeproduct, obtained in an oil was developed on three silica gel thicklayer plates in a mixture of 5% methanol in ethyl acetate. The productwhich had an Rf of 0.5 was scraped off, stirred with methanol andfiltered. The solution was evaporated, and the residue was crystallizedfrom ether to give the pure product as white prisms, mp 186°-189°.

Method B:7-Ethyl-1,9-dimethyl-6-phenyl-9H,9H-imidazo[1,5-a]pyrazolo[4,3-f][1,4]diazepine-3-carboxylicacid, methyl ester

A stirred solution of 0.2 g (0.000567 M) of3-ethyl-1,6-dihydro-α-hydroxyimino-1-methyl-4-phenylpyrazolo[3,4-e][1,4]diazepin-7-aceticacid, methyl ester in 10 ml of dichloromethane and 0.35 ml of aceticacid was treated with 0.4 g (0.0061 M) of zinc dust and stirring wascontinued for 5 min. The mixture was filtered, and the zinc was washedwith dichloromethane and tetrahydrofuran. The combined filtrates werenext treated with 0.3 ml (0.00164 M) of triethylorthoacetate. Themixture was evaporated under reduced pressure and the residue was heatedunder reflux for 1 min in a solution of 15 ml of ethyl acetate whichcontained 0.3 ml of triethylorthoacetate. The solution was evaporatedand developed on 2 thick layer silica gel plates in a solution of ethylacetate containing methanol (10%). The area having an Rf of 0.2-0.4 wasscraped off and washed with methanol. The methanol solution was filteredand evaporated. Crystallization of the residue from ethyl acetate andrecrystallization from a mixture of ethyl acetate and ether gave finalproduct as white rods, m.p. 186°-189°.

EXAMPLE 2288-Chloro-6-(2-chlorophenyl)-1,N,N-trimethyl-4H-imidazo[1,5-a]thieno-[3,2-f][1,4]diazepine-3-carboxamide

Phosphorus pentachloride, 0.46 g (2.2 mmol), was added to a suspensionof 0.785 g (2 mmol) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-3-carboxylicacid in 50 ml of methylene chloride. After stirring under nitrogen in anice bath for 30 min, dimethylamine was introduced until the reactionmixture was alkaline. It was stirred for 30 min at room temperature andwashed with saturated sodium bicarbonate solution, dried and evaporated.Crystallization of the residue from ethyl acetate/ether gave off whitecrystals which were recrystallized from ethyl acetate for analysis, mp197°-200°.

EXAMPLE 229 Ethyl8-chloro-6-(2-fluorophenyl)-1-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A solution of 4.15 g (20.1 mmol) of Ethyl 2-[phenylmethylene)amino]acetate,* N-oxide in 200 ml. of THF was cooled to -73° and 13.2 ml(21.2 mmol) of n-butyl lithium in hexane (MCB) was added slowly dropwiseto give a light orange solution. After 15 min., a solution of 10.15 g(20 mmol) of7-chloro-2-di(morpholino)phosphinyloxy-5-(2-fluorophenyl)-3H-1,4-benzodiazepinein 255 ml of THF was added slowly dropwise and the resulting dark brownsuspension was allowed to warm to room temperature and stir overnight.The mixture was quenched with 3 ml of water and the solvent was removedin vacuo. The residue was diluted with 300 ml of water and extractedrepeatedly with ether; the combined organic layers were washed twicewith water, once with brine, dried with anhydrous magnesium sulfate andconcentrated in vacuo to give the crude product as a light yellow solid.Recrystallization from aqueous acetone gave the product as a whitecrystalline solid.** Concentration of the mother liquor gave a furtheryield of final product.

EXAMPLE 230 Methyl8-chloro-6-(2-chlorophenyl)-1-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A mixture of 8.5 g (0.02 m) of2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepineethanolate, 200 ml of toluene, 4 ml of pyridine-2-carboxaldehyde and 15g of molecular sieves 4A was heated to reflux for 10 min. Followingaddition of 20 g of activated manganese dioxide heating and stirring wascontinued for another 10 min. The mixture was filtered over Celite andthe filtrate was evaporated. Crystallization of the residue fromethylacetate/ether yielded off-white crystals with mp 282°-285°. Theanalytical sample was recrystallized from methylenechloride/ethylacetate, mp 283°-285°.

EXAMPLE 231 Methyl8-chloro-6-(2-chlorophenyl)-1-propyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A mixture of 4.5 g (0.0107 m) of2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepineethanolate, 100 ml of methylene chloride, 2 ml of butylaldehyde and 5 gof molecular sieves 5A was stirred at room temperature for 15 min.Activated manganese dioxide, 10 g, was then added and stirring wascontinued for additional 15 min. The mixture was filtered over Celiteand the filtrate was evaporated. Crystallization of the residue fromether yielded a final product with mp 196°-198°. The analytical samplewas recrystallized from ethylacetate/tetrahydrofuran/hexane, mp197°-198°.

EXAMPLE 232 Methyl8-chloro-6-(2-chlorophenyl)-1-isopropyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Following the procedure of Example 231, but substituting butylaldehydeby isobutylaldehyde gave a final product, crystallized from ether. Foranalysis it was recrystallized from ethylacetate/tetrahydrofuran/hexane,mp 234°-235°.

EXAMPLE 233 Methyl8-chloro-1-chloromethyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A solution of chloroacetaldehyde, 5 ml, which was prepared by heating amixture of 50 ml 2N hydrochloric acid and 50 ml of chloroacetaldehydedimethylacetal for 30 min to reflux, was added to a solution of 4.5 g(0.0107 mol) of2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepineethanolate in 200 ml of methylene chloride. After stirring for 15 min,the reaction mixture was partitioned between methylene chloride andsaturated aqueous sodium bicarbonate solution. The organic phase wasdried and treated with 12 g of activated manganese dioxide. Afterstirring for 15 min at room temperature, the MnO₂ was separated byfiltration over Celite and the filtrate was evaporated. Crystallizationof the residue from methylene chloride/ether yielded the final product.The analytical sample was purified by chromatography over 30 fold amountof silica gel using methylene chloride/ethylacetate 7:3 (v/v). The pureproduct was crystallized from ether, mp 237°-239° dec.

EXAMPLE 234 Methyl8-chloro-6-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Dimethylamine, 5 ml, and 2 ml of acrolein were added to a solution of4.5 g (0.0107 mol) of2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepineethanolate in 100 ml of methylene chloride. After stirring for 10 min atroom temperature, 12 g of activated manganese dioxide was added andstirring was continued for 15 min. The MnO₂ was removed by filtrationover Celite and the filtrate was evaporated. Crystallization of theresidue from ethanol/ether yielded final product which wasrecrystallized from ethylacetate/methanol/hexane for analysis, mp203°-204°.

EXAMPLE 2358-chloro-6-(2-chlorophenyl)-1-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid

A mixture of 4.3 g (0.009 mol) of methyl8-chloro-6-(2-chlorophenyl)-1-(2-pydidyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,200 ml of methanol, 10 ml of water and 1.7 g (0.03 m) of potassiumhydroxide was heated to reflux for 4 hrs. After partial evaporation ofthe solvent, the residue was acidified with glacial acetic acid anddiluted with water. The precipitated product was collected, washed withwater and dried to leave crystalline material which for analysis wasrecrystallized from methylene chloride/methanol/ethylacetate, mp262°-265° dec.

EXAMPLE 2368-chloro-6-(2-chlorophenyl)-1-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Phosphorus pentachloride, 3 g (0.0145 mol) was added to a suspension of4 g (0.0089 mol) of8-chloro-6-(2-chlorophenyl)-1-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 250 ml of methylene chloride cooled by ice/water. After stirringfor 30 min over ice/water, ammonia gas was introduced until the mixtureshowed alcaline reaction. Aqueous ammonia, 20 ml, and 200 ml ofmethylene chloride and then added and stirring was continued for 15 min.The organic layer was separated, dried over sodium sulfate and passedover a pad of silica gel using 5% (v/v) of ethanol in methylenechloride. The solution was evaporated and the residue was crystallizedfrom ethanol/ethylacetate to yield off-white crystals which wererecrystallized for analysis from methylene chloride/ethylacetate, mp255°-257°, reset and melted again at 275°-278°.

EXAMPLE 2378-chloro-6-(2-chlorophenyl)-1-propyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Reaction of 1.5 g (3.5 mmol) of methyl8-chloro-6-(2-chlorophenyl)-1-propyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatewith 20 ml of methanolic ammonia yielded, under the conditions describedin Example 238, a final product, crystallized from methylenechloride/ethanol, mp 298°-300°.

EXAMPLE 2388-chloro-6-(2-chlorophenyl)-1-isopropyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 1.3 g (3 mmol) of methyl8-chloro-6-(2-chlorophenyl)-1-isopropyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylateand 20 ml of methanol containing 20% by weight of ammonia was heated inan autoclave at 130° for 20 hrs. The solvent was evaporated and theresidue was crystallized from methylene chloride/ethanol to give thefinal product with mp 328°-330°. The analytical sample wasrecrystallized from the same solvents.

EXAMPLE 2398-chloro-6-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 0.46 g of methyl8-chloro-6-(2-chlorophenyl)-1-(2-dimethylaminoethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylateand 10 ml of methanol containing 20% of ammonia was heated in the bombfor 20 hours at 130°. The solvent was evaporated and the residue waschromatographed over silica gel (7 g) using 20% of ethanol in methylenechloride. Crystallization of the clean fractions from 2-propanol gavepure product with mp 249°-251°.

EXAMPLE 2408-chloro-6-(2-chlorophenyl)-N-methyl-1-methylaminomethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A solution of methylamine in tetrahydrofuran, 75 ml containing 20%methylamine, was added to a solution of 3 g (6.9 mmol) of methyl8-chloro-1-chloromethyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 50 ml of tetrahydrofuran.The mixture was heated to 100° for 118 hrs in a sealed vessel. Thesolvent was evaporated and the residue was crystallized from ethanol toyield final product which was purified by chromatography over 50 g ofsilica gel using 5% (v/v) of ethanol in methylene chloride. The combinedclean fractions gave after evaporation and crystallization frommethylene chloride/ethanol, product with mp 270°-273°.

EXAMPLE 241 Methyl1-Aminomethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,hydrochloride

A solution of 2.4 g (5.4 mmol) of methyl1-azido-methyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 50 ml of tetrahydrofuran and 50 ml of ethanol was hydrogenated for 2hrs at atmospheric pressure with Raney nickel as catalyst. The catalystwas removed by filtration and the filtrate was evaporated. The residuewas dissolved in 2-propanol and the solution was treated with 5 mmol ofethanolic hydrogen chloride. The precipitated hydrochloride wascollected and recrystallized from 2-propanol/methanol to yield productwith mp 265°-270° dec. The analytical sample was recrystallized from thesame solvents, mp 270°-275° dec.

EXAMPLE 242 Methyl8-chloro-6-(2-chlorophenyl)-1-dimethylaminomethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A mixture of 0.435 g (1 mmol) of methyl8-chloro-1-chloromethyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,15 ml of tetrahydrofuran and 1.5 ml of dimethylamine was heated in asealed tube at 100° for 3 hours. The solvent was evaporated and theresidue was partitioned between methylene chloride and aqueous sodiumbicarbonate solution. The orgnic phase was dried and evaporated and theresidue was crystallized from ether to yield final product. Theanalytical sample was recrystallized from ethylacetate/hexane mp181°-183°.

EXAMPLE 243 Methyl1-azidomethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A mixture of 2.18 g (5 mmol) of methyl8-chloro-1-chloromethyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,0.65 g (10 mmol) of sodium azide and 30 ml of dimethylformamide washeated to reflux for 5 min. The product was precipitated by addition ofwater, was collected and dissolved in methylene chloride. The solutionwas dried and evaporated. Crystallization from ethylacetate/etheryielded colorless crystals with mp 187°-189°. The analytical sample wasrecrystallized from ethylacetate/hexane, mp 188°-190°.

EXAMPLE 244 Methyl1-acetoxymethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A mixture of 0.435 g (1 mmol) of methyl8-chloro-1-chloromethyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,0.5 g of sodium acetate and 20 ml of dimethyl formamide was heated toreflux for 10 min under an atmosphere of nitrogen. The solvent wasremoved under reduced pressure and the residue was partitioned betweenwater and methylene chloride. The methylene chloride layer was dried andevaporated and the residue was chromatographed over 7 g of silica gelusing 30% (v/v) of ethylacetate in methylene chloride. Crystallizationof the combined clean fractions from ether yielded final product with mp186°-188°. For analysis it was recrystallized from methylenechloride/ether/hexane.

EXAMPLE 2451-Aminomethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidehydrochloride hemihydrate hemiisopropanolate

A solution of 2 g (4.65 mmol) of1-azidomethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidein 150 ml of tetrahydrofuran and 75 ml of ethanol was hydrogenated for11/2 hours at atmospheric pressure with Raney nickel as catalyst. Thecatalyst was separated by filtration and the filtrate was evaporated.Crystallization from ethanol/ether yielded final product with mp230°-235° which was converted to the hydrochloride as follows: 1.2 g ofthe above base was dissolved in a mixture of hot ethanol and methanol.Ethanolic hydrogen chloride (3 mmol) was added. The mixture wasconcentrated and the hydrochloride was crystallized by addition ofisopropanol and cooling. The crystals were collected, washed with2-propanol and ether to leave product with mp 250°-260°. The analyticalsample was recrystallized from methanol/2-propanol to give crystalswhich analyzed for a hemihydrate hemiisopropanolate, mp 250°-260°undefined.

EXAMPLE 2468-chloro-6-(2-chlorophenyl)-1-dimethylaminoethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 0.44 g (1 mmol) of methyl8-chloro-6-(2-chlorophenyl)-1-dimethylaminomethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylateand 15 ml of methanol containing 20% of ammonia was heated for 16 hrs at130° in an autoclave. The solvent was evaporated and the residue wascrystallized from ethanol/ether to yield final product. The analyticalsample was purified by passing over silica gel using methylenechloride/ethylacetate 1:1 (v/v) and crystallization from ethylacetate,mp 242°-245°.

EXAMPLE 2471-Azidomethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 4.4 g (0.01 mol) of methyl1-azidomethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,200 ml of methanol, 10 ml of water and 1.7 g (0.03 mol) of potassiumhydroxide was heated to reflux for 3 hrs. After partial evaporation themixture was acidified with glacial acetic acid and diluted with water.The precipitated product was collected and dissolved in methylenechloride. The solution was dried and evaporated and the residue wascrystallized from methylene chloride/ethylacetate/hexane to yield1-azidomethyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid which was converted to the amide as follows: Phosphoruspentachloride 2.1 g (0.01 mol) was added to a suspension of the abovematerial in 200 ml of methylene chloride and the mixture was stirred inice-water for 20 min. A stream of ammonia was then introduced until thereaction mixture was alcaline. After stirring for an additional 15 min,aqueous ammonia was added and stirring was continued for 1 hr at roomtemperature. The mixture was diluted with methylene chloride and washedwith saturated sodium chloride solution. The organic phase was dried andevaporated. The residue was chromatographed over 120 g of silica gelusing 2.5% (v/v) of ethanol in methylene chloride. The clean fractionswere combined and evaporated and the residue was crystallized fromethanol to yield final product with mp 258°-260° dec. The analyticalsample was recrystallized from methylene chloride/ethylacetate.

EXAMPLE 248 Methyl8-chloro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

Raney nickel, 2 teaspoonsful, was added to a solution of 10 g (0.028mol) of7-chloro-alpha-hydroximino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid,methyl ester in a mixture of 200 ml of methanol and 200 ml oftetrahydrofuran. The mixture was hydrogenated at atmospheric pressurefor 5 hrs. The catalyst was separated by filtration over Celite and thefiltrate was evaporated to dryness. The residue was dissolved in 100 mlof methanol and the solution was treated with 10 ml of triethylorthoformate and 5 ml of ethanolic hydrogen chloride. After refluxingthe mixture for 10 min the solvent was evaporated under reduced pressureand the residue was partitioned between methylene chloride and saturatedaqueous sodium bicarbonate solution. The organic phase was dried andevaporated. Crystallization of the residue from ether yielded finalproduct which was recrystallized from methylene chloride/ether foranalysis, mp 235°-236°.

EXAMPLE 249 Methyl8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

A mixture of 9 g of 2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepineethanolate, 100 ml of toluene and 20 ml of triethyl orthoformate washeated to reflux for 15 min. The solvent was evaporated under reducedpressure and the crystalline residue was collected with ether andrecrystallized from ethylacetate/methanol to yield final product with mp206°-208°.

EXAMPLE 2508-chloro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 5 g of methyl8-chloro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and100 ml of methanol containing 20% of ammonia was heated to 130° in anautoclave for 8 hrs. The precipitated crystals were collected andrecrystallized from tetrahydrofuran/methanol to yield final product withmp 295°-296°. The analytical sample was recrystallized fromdimethylformamide/ether, mp 296°-297°.

EXAMPLE 2518-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Phosphorus pentachloride, 2.6 g (0.0125 m) was added to a suspension of3.55 g (0.01 m) of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 200 ml of methylene chloride cooled with ice/water. Afterstirring for 30 min ammonia gas was introduced until the reactionmixture was alkaline. After additional 15 min aqueous ammonia was addedand stirring was continued for 30 min. The reaction mixture was thenpartitioned between water and methylene chloride containing 10% (v/v) ofethanol. The organic phase was dried and passed over a pad of silicagel. The solution was evaporated and the solid residue wasrecrystallized from ethanol to yield the final product. The analyticalsample was recrystallized from tetrahydrofuran/ethanol, mp 292°-294°.

EXAMPLE 2528-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3carboxamide

A mixture of 5 g (0.013 mol) of methyl8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylateand 75 ml of methanol containing 20% of ammonia was heated in anautoclave at 130° for 18 hrs. The reaction mixture from which theproduct had crystallized was heated in methanol/methylene chloride untilsolution was complete. Filtration and concentration yielded the finalproduct with mp >300°. The analytical sample was recrystallized frommethylene chloride/ethanol.

EXAMPLE 2538-chloro-N,N-dimethyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 5 g (0.014 mol) of methyl8-chloro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,2.4 g (0.043 mol) of potassium hydroxide, 10 ml of water and 140 ml ofmethanol heated to reflux for 6 hrs. The solvent was evaporated and theresidue was dissolved in water. The solution was filtered and acidifiedwith glacial acetic acid. The precipitated crystals were collected andcrystallized from methylene chloride/ethanol to give8-chloro-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acidwith mp 268°-270°.

1 g of this acid was stirred with 1.3 g of phosphorus pentachloride and100 ml of methylene chloride at room temperature for 2 hrs.Dimethylamine was bubbled into the mixture with cooling until a clearsolution with basic pH resulted. The solution was then washed withsodium chloride solution and water. The methylene chloride layer wasdried and evaporated.

Crystallization of the residue from ether yielded the final productwhich was recrystallized from methylene chloride/ethylacetate foranalysis, mp 231°-233°.

EXAMPLE 2548-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 2 g of methyl8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate,15 ml of hexamethyl phosphoric triamide and 1.5 g of lithium chloridewas heated to 225°. The cooled reaction mixture was partitioned betweenwater and methylene chloride/ether. The organic phase was washed withaqueous bicarbonate solution, was dried and evaporated. Crystallizationfrom ether yielded the final product which was recrystallized fromethylacetate/methanol for analysis, mp 240°-242°.

EXAMPLE 2558-chloro-6-(2-chlorophenyl)-3-hydroxymethyl-4H-imidazo[1,5-a][1,4]benzodiazepineisopropanolate

A solution of 25 g (0.065 mol) of methyl8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylatein 250 ml of tetrahydrofuran was added at -10° to a suspension of 5 g oflithium aluminum hydride in 200 ml of ether. After addition the mixturewas stirred between -5° and 0° for 15 min. The mixture was thenhydrolized by addition of 25 ml of water. The inorganic material wasseparated by filtration over Celite and the filtrate was dried andevaporated. Crystallization of the residue from methylenechloride/ether/ethylacetate yielded the solvated product.Recrystallization from 2-propanol/ether gave a solvate with mp 103°-105°dec. which according to analytical and spectral data contained 1 mol ofisopropanol.

EXAMPLE 2568-chloro-6-(2-chlorohenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3carboxaldehyde

A mixture of 0.5 g of8-chloro-6-(2-chlorophenyl)-3-hydroxymethyl-4H-imidazo[1,5-a][1,4]benzodiazepineisopropanolate, 40 ml of methylene chloride and 2.5 g of activatedmanganese dioxide was stirred at room temperature for 2 hrs. The MnO₂was removed by filtration over Celite and the filtrate was evaporated.Crystallization of the residue from ether gave the final product with mp213°-215°.

EXAMPLE 2578-chloro-3-chloromethyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

Crude8-chloro-6-(2-chlorophenyl)-3-hydroxymethyl-4H-imidazo-[1,5-a][1,4]benzodiazepine,6 g, was added slowly to 30 ml of thionyl chloride. Following additionthe mixture was stirred for 15 min at room temperature and thengradually diluted with 100 ml of ethylacetate. The precipitate crystalswere collected after 15 min and partitioned between methylene chlorideand saturated aqueous sodium bicarbonate solution. The methylenechloride layer was dried and evaporated. Crystallization from methylenechloride/ether yielded the final product. The analytical sample waspurified by passing over silica gel using 10° (v/v) of ethylacetate inmethylene chloride followed by crystallization from ether, mp ca. 165°.The crystals do not melt upon slow heating but on immersion at about165°.

EXAMPLE 2583-acetyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 2.8 g (7.8 mmol) of8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehydein 150 ml of tetrahydrofuran was added to 50 ml of a 1 molar solution ofmethyl magnesium iodide in ether. After stirring for 15 min at roomtemperature the reaction mixture was hydrolysed by addition of water,diluted with tetrahydrofuran dried over sodium sulfate and filtered overCelite. The filtrate was evaporated and the residue was chromatographedover 60 g of silica gel using 5% (v/v) of ethanol in methylene chloride.The clean fractions containing8-chloro-6-(2-chlorophenyl)-3-(1-hydroxyethyl)-4H-imidazo[1,5-a][1,4]benzodiazepinewere combined and evaporated. The residue was dissolved in 100 ml ofmethylene chloride and stirred for 2 hrs at room temperature afteraddition of 15 g of activated manganese dioxide. The MnO₂ was removed byfiltration over Celite and the filtrate was evaporated. The residue wasagain purified by chromatography over 30 g of silica gel using 10% (v/v)of ethylacetate in methylene chloride. Crystallization of the combinedclean fractions from ethylacetate/hexane gave the final product with mp214°-216°.

EXAMPLE 2598-Chloro-6-(2-chlorophenyl)-3-methoxymethyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 2.7 g (7.15 mmol) of8-chloro-3-chloromethyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine,50 ml of methanol and 3 ml of triethylamine was heated to reflux for 20min. The solvent was evaporated and the residue was partitioned betweenmethylene chloride and 10% aqueous sodium carbonate solution. Themethylene chloride layer was dried and evaporated and the residue wasdissolved in 2-propanol and treated with ethanolic hydrogen chloride.The crystalline dihydrochloride with mp >230° dec. which precipitatedwas collected and partitioned between methylene chloride and aqueoussodium carbonate solution. The organic phase was dried and evaporatedand the residue was crystallized from ether/hexane to yield finalproduct with mp 126°-130°. The analytical sample was recrystallized fromether.

EXAMPLE 2608-chloro-6-phenyl-1,N,N-trimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 1.5 g (4.2 mmol) of8-chloro-1-methyl-6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, 1.7 g (8 mmol) of phosphorus pentachloride and 100 ml of methylenechloride was stirred under argon for 3 hrs. Dimethylamine was introducedat room temperature until a clear solution with basic pH resulted. Thesolution was washed with water, dried and evaporated. Crystallization ofthe residue from ethylacetate/ether/hexane and recrystallization fromether gave final product with mp 173°-175°.

EXAMPLE 2618-chloro-6-(2-fluorophenyl)-1-methyl-N-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Phosphorus pentachloride, 1.3 g (6.25 mmol) was added to a suspension of1.9 g (5 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 100 ml of methylene chloride. After stirring for 30 min withcooling over ice/water, 7 ml of aniline was added and stirring wascontinued for 30 min at room temperature. The reaction mixture waspartitioned between 10% aqueous sodium carbonate solution and methylenechloride. The organic layer was dried and evaporated. Crystallization ofthe residue from ether and recrystallization from methylenechloride/ethanol gave a final product which was recrystallized fromtetrahydrofuran/ethanol for analysis, mp 228°-288°.

EXAMPLE 2628-chloro-N-cyclopropyl-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

Phosphorus pentachloride, 1.3 g (6.25 mmol) was added to a suspension of1.9 g (5.1 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 100 ml of methylene chloride. After stirring for 30 min overice/water 3 ml of cyclopropylamine was added and stirring was continuedfor 10 min. The reaction mixture was washed with aqueous sodiumcarbonate solution, dried and evaporated. The residue was passed over apad of silica gel using 10% (v/v) of ethanol in methylene chloride.Crystallization of the product from ethylacetate/hexane yielded finalproduct as crystals with mp 196°-197°.

EXAMPLE 2638-chloro-6-(2-chlorophenyl)-1,N,N-trimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A stirred suspension of 3.6 g (0.0093 mole) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 75 ml of dichloromethane was cooled in an ice bath and treatedwith 2.1 g (0.01 mole) of phosphorus pentachloride in portions. Thereaction was protected by a drying tube and stirring in the cold wascontinued 30 min. longer. With continued cooling dimethylamine wasbubbled into the solution for 5 minutes and stirring was continued foran additional 30 min. The mixture was evaporated at reduced pressure todryness. The gummy residue was stirred with water and basified withammonium hydroxide. Extraction with methylene chloride followed bydrying and evaporation in vacuo gave a tan foam. The foam was dissolvedin 600 ml of boiling ether and filtered to remove some insolublematerial. After concentrating the filtrate on a steam bath to about 250ml, it was filtered again. Further concentration to about 100 ml withoccasional scratching initiated crystallization. The flask was removedfrom the heat and cooled at room temperature overnight. The off-whiteprisms were filtered, washed with ether and air dried on the funnel tofinal product with mp 225°-230°. Recrystallization of a sample frombenzene-ether raised the melting point to 228°-232°.

EXAMPLE 2648-chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 2,2-dimethylhydrazide

A mixture of 1.2 g (2.9 mmol) of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, 2,2-dimethylhydrazide, 50 ml of methylene chloride, 5 ml ofglacial acetic acid and 2.5 g of zinc dust was stirred at roomtemperature for 2 hrs. The inorganic material was separated. Thefiltrate was washed with sodium carbonate solution, dried andevaporated. The residue was crystallized from ethylacetate/ether toyield a final product which was recrystallized from ethylacetate foranalysis, mp 218°-219°.

EXAMPLE 2658-chloro-6-(2-chlorophenyl)-5,6-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A stirred solution of 7 g (0.018 mole) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidein 70 ml of glacial acetic acid was treated with 5.6 g (0.087 g. atm.)of zinc dust in portions. The stirred mixture was heated under argon inan oil bath at 110° for 5 hrs. After cooling to room temperature themixture was filtered and the solid was washed with methylene chloride.The filtrate was concentrated at reduced pressure at 60° to removemethylene chloride and the residue was poured into cold water andbasified with ice cold ammonia. The resulting white solid was filtered,washed with water and partially dried on the funnel. Treatment of thedamp solid with 200 ml of 1 N hydrochloric acid by stirring for 5 minand then filtering gave about 3 g of unreacted material as a whitesolid. When the filtrate was basified with cold, dilute ammoniumhydroxide a white solid separated which was collected by filtration,washed with water and air dried on the funnel to give final product.

Recrystallization from ethanol-methylene chloride gave white plates,m.p. 298°-305° dec.

EXAMPLE 2668-chloro-6-(2-chlorophenyl)-5,6-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidehydrochloride 11/3 hydrate

A suspension of 1.3 g (0.0034 mole) of the base of Example 265 in 75 mlof 95% ethanol was treated with 10 ml of a 5.7 N solution of hydrogenchloride in ethanol and boiled on a steam bath to give a clear solution.The solution was filtered and kept at room temperature overnight. Whiteneedles had separated. The product was filtered, washed with ethanol andair dried to give final product, mp 310°-315° dec. after changing toprisms at ca. 250°. Another amount of product, mp 305°-310° dec. wasobtained by concentrating the mother liquor.

EXAMPLE 2678-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,and8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 185 mg of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid in 5 ml of ethylene glycol was heated to reflux for 1 hr under anatmosphere of nitrogen. The cooled reaction mixture was partitionedbetween ether/toluene and saturated sodium bicarbonate solution. Theorganic phase was separated, dried and evaporated. The residue waschromatographed over 7 g of silica gel using 3% (v/v) of ethanol inmethylene chloride to yield both the less polar8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepinewith mp 177°-179° and8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinewith mp 151°-153°.

EXAMPLE 2688-chloro-6-(2-chlorophenyl)-1,3-dimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Raney nickel, 40 g, was added to a solution of 3.9 g (0.01 m) of8-chloro-3-chloromethyl-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepinein 125 ml of dry tetrahydrofuran. After stirring at room temperature for15 min the nickel was separated by filtration over Celite and thefiltrate was evaporated. Crystallization of the residue fromether/hexane yielded crystals with mp 175°-177°. The analytical samplewas recrystallized from methylene chloride/hexane and had the same mp.

EXAMPLE 2698-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-aceticacid, ethyl ester

A mixture of 0.38 g (1 mmol) of8-chloro-6-(2-chlorophenyl)-3-cyanomethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepineand 10 ml of ethanol containing 10% of hydrogen chloride was heated toreflux for 30 min. The reaction mixture was then partitioned betweenmethylene chloride and 10% aqueous sodium carbonate solution. Theorganic phase was dried and evaporated and the residue was crystallizedfrom ether/hexane to yield product with mp 143°-154°. The analyticalsample was recrystallized from ethanol/hexane and had the same mp.

EXAMPLE 2708-chloro-6-(2-chlorophenyl)-3-(2-hydroxyethyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 0.43 g (1 mmol) of8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-aceticacid, ethyl ester in 10 ml of tetrahydrofuran was added to a suspensionof 0.3 g of lithium aluminum hydride in 30 ml of ether cooled to -10°.Following the addition the mixture was stirred at 0° to 5° for 10 minand then hydrolysed by addition of water. The inorganic material wasseparated by filtration and washed with methylene chloride. The filtratewas dried and evaporated. Crystallization of the residue from ethylacetate/ether yielded product, which was further purified bychromatography over 5 g of silica gel using 5% (v/v) of ethanol inmethylene chloride and crystallized from ethyl acetate/hexane, mp170°-171°.

We claim:
 1. A process to produce a compound of the formula ##STR94##wherein A is ##STR95## R₁ is selected from the group consisting ofhydrogen, lower alkyl, alkoxy lower alkyl, halo lower alkyl; R ishydrogen or lower alkyl; R₃ is selected from the group consisting ofhydrogen and lower akyl; R₄ is selected from the group consisting ofhydrogen, halogen, cyano, trifluoromethyl, lower alkyl, mono- or di-C₁to C₇ alkyl or phenyl, chlorophenyl or tolyl substituted amino, amino,hydroxy lower alkyl and lower alkanoyl; R₆ is selected from the groupconsisting of phenyl, mono-halo or mono-nitro substituted phenyl,di-halo or halo-nitro substituted phenyl, pyridyl and mono-halo ormono-nitro substituted pyridyl; and ##STR96## is selected from the groupconsisting of ##STR97## which comprises the stepwise reaction of acompound of the formula ##STR98## wherein R₃, R₄, R₆, A and ##STR99##are as above and the leaving group is selected from the group consistingof alkoxides, alkylthio, halo, cyano, phosphate and nitrosoalkylamino(a)with the anion generated from malonic ester, i.e., a compound of theformula ##STR100## wherein R is lower alkyl; (b) decarboxylating with analkali metal hydroxide the product of (a); (c) nitrosating with nitrousacid the product of (b); (d) reducing with H₂ /Raney nickel orzinc/acetic acid the product of (c); (e) reacting the product of (d)with an alkanoic acid ortho ester of the formula

    R.sub.1 C(OR).sub.3

wherein R is lower alkyl and R₁ is selected from the group consisting ofhydrogen, lower alkyl, alkoxy lower alkyl, halo lower alkyl, to producethe final product as an ester, i.e., R=lower alkyl; (f) if desired,hydrolysing with alkali metal hydroxides the product of (e) to the finalproduct as as acid, i.e., R=hydrogen.